Neurologyhttp://n.neurology.org/icons/banner/title.gifhttp://n.neurology.org
http://n.neurology.org/cgi/content/short/94/22/947?rss=1
2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009562hwp:resource-id:neurology;94/22/947American Academy of Neurology2020-06-02IN FOCUS9422947948
hw_mjid:neurology;94/22/947
http://n.neurology.org/cgi/content/short/94/22/949?rss=1
The emergence of novel coronavirus 2019 (COVID-19)1 and the subsequent pandemic present a unique challenge to neurologists managing patients with multiple sclerosis (MS) and related neuroinflammatory disorders, such as neuromyelitis spectrum disorder (NMOSD).
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009507hwp:master-id:neurology;WNL.0000000000009507American Academy of Neurology2020-06-02SPECIAL EDITORIALS9422949952
hw_mjid:neurology;94/22/949
http://n.neurology.org/cgi/content/short/94/22/953?rss=1
Autoimmune neurology has become an exciting subspecialty due to the discovery of antibody biomarkers that have defined a spectrum of treatable neurologic syndromes with new-onset movement disorders, psychosis, cognitive decline, and seizures in both adults and children. After autoantibodies are discovered, however, subsequent descriptions often broaden the phenotypic spectrum of the disease. In children, the most common autoantibody-associated CNS syndromes are N-methyl-D-aspartate receptor (NMDAR)– and myelin oligodendrocyte glycoprotein (MOG) antibody–associated diseases.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009521hwp:master-id:neurology;WNL.0000000000009521American Academy of Neurology2020-06-02EDITORIALS9422953954
hw_mjid:neurology;94/22/953
http://n.neurology.org/cgi/content/short/94/22/955?rss=1
Despite extensive characterization of the role of platelet activation and the coagulation cascade in acute ischemic stroke (AIS), few studies have analyzed the immune cell composition of AIS thrombi. Recent articles describing a function of neutrophil-derived extracellular nucleosomes (NETs) in thrombus formation9 highlight the great need for clinical immunohistologic analyses in acute vascular disease. In this issue of Neurology®, Novotny et al.1 conduct a study comparing thrombus histology between AIS and acute myocardial infarction (AMI), with a focus on the role of immune cells and NETs.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009529hwp:master-id:neurology;WNL.0000000000009529American Academy of Neurology2020-06-02EDITORIALS9422955956
hw_mjid:neurology;94/22/955
http://n.neurology.org/cgi/content/short/94/22/957?rss=1
Multiple sclerosis (MS) is characterized by a plethora of symptoms, including cognitive impairment. The prevalence of cognitive impairment ranges from 40% to 70%,1,2 varying with age, disease duration, physical disability,3 and the number and types of domains tested. Information processing speed has historically been considered the most commonly affected cognitive domain,1 but episodic memory, executive function, and language functions may also be affected. The adverse influence of cognitive impairment is substantial. Affected individuals are less likely to maintain employment or retain the ability to drive, participate in society, or remain independent4; 70% of individuals with MS residing in long-term care facilities have cognitive impairment.5 Current treatment guidelines for MS place a strong emphasis on early diagnosis and early institution of disease-modifying therapies (DMTs). The goals of these therapies include the reduction of relapses, new lesions on MRI, and disability progression. People with MS and clinicians also identify preservation of cognition as an important desired outcome of DMT use.6 Remarkably, although the first DMT was approved 25 years ago, and more than 10 DMTs are available now, we still lack a concrete understanding of whether these therapies reduce the progression of cognitive impairment.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009524hwp:master-id:neurology;WNL.0000000000009524American Academy of Neurology2020-06-02EDITORIALS9422957958
hw_mjid:neurology;94/22/957
http://n.neurology.org/cgi/content/short/94/22/959?rss=1
The coronavirus 2019 (COVID-19) pandemic has potential to disproportionately and severely affect patients with neuromuscular disorders. In a short period of time, it has already caused reorganization of neuromuscular clinical care delivery and education, which will likely have lasting effects on the field. This article reviews (1) potential neuromuscular complications of COVID-19, (2) assessment and mitigation of COVID-19-related risk for patients with preexisting neuromuscular disease, (3) guidance for management of immunosuppressive and immunomodulatory therapies, (4) practical guidance regarding neuromuscular care delivery, telemedicine, and education, and (5) effect on neuromuscular research. We outline key unanswered clinical questions and highlight the need for team-based and interspecialty collaboration. Primary goals of clinical research during this time are to develop evidence-based best practices and to minimize morbidity and mortality related to COVID-19 for patients with neuromuscular disorders.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009566hwp:master-id:neurology;WNL.0000000000009566American Academy of Neurology2020-06-02INVITED ARTICLE9422959969
hw_mjid:neurology;94/22/959
http://n.neurology.org/cgi/content/short/94/22/979?rss=1
Articles appearing in the June 2019 issue
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009528hwp:resource-id:neurology;94/22/979American Academy of Neurology2020-06-02WHAT'S HAPPENING9422979979
hw_mjid:neurology;94/22/979
http://n.neurology.org/cgi/content/short/94/22/980?rss=1
Articles appearing in the September 2019 issue
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009527hwp:resource-id:neurology;94/22/980American Academy of Neurology2020-06-02WHAT'S HAPPENING9422980980
hw_mjid:neurology;94/22/980
http://n.neurology.org/cgi/content/short/94/22/981?rss=1
Nicte I. Mejia, MD MPH FAAN, Nicole Rosendale, MD, Jeffrey McClean II, MD
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009531hwp:resource-id:neurology;94/22/981American Academy of Neurology2020-06-02WHAT'S HAPPENING9422981981
hw_mjid:neurology;94/22/981
http://n.neurology.org/cgi/content/short/94/22/982?rss=1
One in 6 Americans live with a neurologic disease.1–3 Recent evidence suggests that the number of people dying from and affected by these disorders has increased substantially in the past 25 years, contributing to a higher health loss across the lifespan.2 The American Academy of Neurology's (AAN's) mission is in part to promote the highest-quality patient-centered neurologic care for these patients, and the AAN's leadership in quality improvement initiatives and developing outcome measures is a conveyance of this mission. Quality, as defined by the National Academy of Medicine, is "the degree to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge."4 Quality improvement is "systematic, data-guided activities designed to bring about immediate improvements in health care delivery" and is considered "an intrinsic part of normal health care operations."5 Data from outcome measures can be effectively used to establish a baseline of care quality delivered within a given health care unit (e.g., multispecialty group)5,6 and guide the implementation and ongoing evaluation of quality improvement initiatives intended to improve care quality and delivery.6 Increasing demands to provide health care outcomes data from patients and payers and the need for neurologic providers to have these data available to assist in care planning necessitated the AAN's former Quality and Safety Subcommittee to recommend the seating of a small work group to develop neurologic outcome quality measures, which would be applicable broadly across major neurologic diseases.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009525hwp:master-id:neurology;WNL.0000000000009525American Academy of Neurology2020-06-02SPECIAL ARTICLE9422982990
hw_mjid:neurology;94/22/982
http://n.neurology.org/cgi/content/short/94/22/991?rss=1
There is increasing evidence that patients with neurosarcoidosis who respond incompletely to immunosuppression and corticosteroids do so with TNFα blockade.1,2 It appears that around 20% of those with severe CNS disease require treatment with TNFα antagonists; around 8% of those with neurosarcoidosis. Treatment is required for around 3 years; shorter courses often result in disease relapse at the same site.2
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009526hwp:master-id:neurology;WNL.0000000000009526American Academy of Neurology2020-06-02CLINICAL/SCIENTIFIC NOTES9422991993
hw_mjid:neurology;94/22/991
http://n.neurology.org/cgi/content/short/94/22/994?rss=1
A 25-year-old woman presented to the neurology clinic describing 3 episodes of transient loss of consciousness over 9 months. The first 2 were unwitnessed, with no prodromal symptoms. The third event was a witnessed collapse while shopping. It was reported that both the patient's arms were stiff and by her sides with accompanied lateral tongue biting, a blue discoloration to her face, choking noises, and dilated pupils. The event lasted for less than 2 minutes, after which she was confused and drowsy. She remembered a premonitory feeling before the third collapse but found this difficult to describe.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009533hwp:master-id:neurology;WNL.0000000000009533American Academy of Neurology2020-06-02RESIDENT &amp;amp; FELLOW SECTION9422994999
hw_mjid:neurology;94/22/994
http://n.neurology.org/cgi/content/short/94/22/1000?rss=1
In "The two lives of neurologist Helmut J. Bauer (1914–2008): Renowned MS specialist and National Socialist," Schmidt et al. provided a historical narrative of Helmut Bauer, who was a Nazi with a prominent position in the Reich Physicians' Chamber and a renowned neurologist. Brenner noted that, like Bauer, Dr. Viktor Frankl had dichotomous identities during the WWII era; however, Frankl was simultaneously a concentration camp doctor and inmate. Schmidt astutely points out that Frankl was, unfortunately, unique, as while most Nazi physicians were able to excel after WWII, many Jewish physicians were forced to relocate and were unable to return to their medical careers. Reiber et al. disputed Schmidt et al.'s claims that Bauer was a criminal and argued that his reputation has inappropriately been maligned. Schmidt and Gross respond that although their perspective is unbiased, Reiber et al.'s views are colored by their personal relationship with Bauer. However, although their perspectives on Bauer conflict, they value the role for academic discourse about historical topics, particularly events that occurred during the Nazi reign.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009536hwp:resource-id:neurology;94/22/1000American Academy of Neurology2020-06-02DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE942210001000
hw_mjid:neurology;94/22/1000
http://n.neurology.org/cgi/content/short/94/22/1000-a?rss=1
I appreciate the article concerning the 2 lives of neurologist Helmet Bauer who, although involved in Nazi war crimes and even being in the SS, still was able—following denazification—to lead a productive career helping patients with multiple sclerosis.1
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009535hwp:resource-id:neurology;94/22/1000-aAmerican Academy of Neurology2020-06-02DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE942210001000
hw_mjid:neurology;94/22/1000-a
http://n.neurology.org/cgi/content/short/94/22/1001?rss=1
We thank Dr. Brenner for the comment on our historical neurology paper.1 In fact, most university teachers with a Nazi past had no difficulties in continuing or even expanding their careers in postwar Germany.2 This is also shown by Helmut Bauer's example.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009538hwp:resource-id:neurology;94/22/1001American Academy of Neurology2020-06-02DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE942210011001
hw_mjid:neurology;94/22/1001
http://n.neurology.org/cgi/content/short/94/22/1001-a?rss=1
In the Historical Neurology article by Schmidt et al.,1 the authors try to trace HJ Bauers' "exact activities and tasks during the second world war" and conclude that "Bauer was actively involved in Nazi crimes." However, we only find general references to the Nazi crimes. "He must have been aware," a repeated argument of the authors,1 is not yet evidence of criminal action. Our own search for documents2–6 gives a different impression. Neither "surprisingly" nor an "unusual step," as the authors claim, HJB came to Berlin in 1932 as a scholarship holder for medicine from the Verein für das Deutschtum im Ausland, because his parents could not finance this in the United States. He married a German physician in 1940; the same year he became a German citizen. This is really an alternative motive to the Nazi conviction the authors have suggested.1
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009539hwp:resource-id:neurology;94/22/1001-aAmerican Academy of Neurology2020-06-02DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE942210011002
hw_mjid:neurology;94/22/1001-a
http://n.neurology.org/cgi/content/short/94/22/1002?rss=1
We thank Reiber et al. for their comment on our article.1 Unlike us, you have known and appreciated Helmut J. Bauer personally. We do understand that it is difficult to reconcile the positive personal image that you have gained with our specialist research. We encounter such difficulties of companions and academic students of examined persons again and again.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009540hwp:resource-id:neurology;94/22/1002American Academy of Neurology2020-06-02DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE942210021003
hw_mjid:neurology;94/22/1002
http://n.neurology.org/cgi/content/short/94/22/e2290?rss=1
Objective

To delineate autoimmune disease in association with contactin-associated protein 2 (CASPR2) antibodies in childhood, we reviewed the clinical phenotype of children with CASPR2 antibodies.

High-titer CASPR2 antibodies are associated with Morvan syndrome in children as young as 2 years. However, CASPR2 autoimmunity mimics systemic disease and hypertensive encephalopathy in children younger than 7 years. The outcome following immunotherapy was mostly favorable; long-term behavioral impairment may occur in younger children.

Between 4% and 7.5% of patients with anti-NMDAR encephalitis have concurrent glial-Ab or NS-Ab. Some of these antibodies (MOG-Ab, AQP4-Ab, NS-Ab) confer additional clinical-radiologic features and may influence prognosis.

To evaluate the efficacy and safety of adjunctive cenobamate 200 mg/d in patients with uncontrolled focal (partial-onset) seizures despite treatment with 1 to 3 antiepileptic drugs.

Methods

In this multicenter, double-blind, placebo-controlled study, adults 18 to 65 years of age with focal seizures were randomized 1:1 (cenobamate:placebo) after an 8-week baseline period. The 12-week double-blind treatment period consisted of a 6-week titration phase and a 6-week maintenance phase. The primary outcome was percent change in seizure frequency (from baseline) per 28 days during double-blind treatment.

Evolution of SpO2 after 1,352 DES was analyzed in 75 patients with refractory focal epilepsy who underwent stereo-EEG recordings. For each DES, we assessed the change in SpO2 from 30 seconds prior to DES onset to 120 seconds following the end of the DES. The primary outcome was occurrence of stimulation-induced transient hypoxemia as defined by decrease of SpO2 ≥5% within 60 seconds after stimulation onset as compared to pre-DES SpO2 or SpO2 nadir <90% during at least 5 seconds. Localization of the stimulated contacts was defined according to MarsAtlas brain parcellation and Freesurfer segmentation.

Results

A stimulation-induced transient hypoxemia was observed after 16 DES (1.2%) in 10 patients (13%), including 6 in whom SpO2 nadir was <90%. Among these 16 DES, 7 (44%) were localized within the perisylvian cortex. After correction for individual effects and the varying number of DES contributed by each person, significant decrease of SpO2 was significantly associated with the localization of DES (p = 0.019).

Conclusion

Though rare, a significant decrease of SpO2 could be elicited by cortical direct electrical stimulation outside the temporo-limbic structures, most commonly after stimulation of the perisylvian cortex.

Because little is known about associations between biomarkers of vascular injury and stroke risk, we evaluated associations between plasma concentrations of 6 novel biomarkers of vascular injury and stroke risk in a population-based study.

In this population-based study, circulating levels of ICAM3, an adhesion molecule shed by leukocytes, were associated with increased risk of incident stroke. Further mechanistic studies are needed to elucidate the pathophysiology underlying this association.

To investigate whether immune cell composition and content of neutrophil extracellular traps (NETs) in relation to clinical outcome are different between acute ischemic stroke (AIS) and acute myocardial infarction (AMI), we performed histologic analysis and correlated results with clinical and procedural parameters.

Methods

We retrieved thrombi from patients with AIS (n = 71) and AMI (n = 72) during endovascular arterial recanalization and analyzed their immune cell composition and NET content by immunohistology. We then associated thrombus composition with procedural parameters and outcome in AIS and with cardiac function in patients with AMI. Furthermore, we compared AIS thrombi with AMI thrombi and differentiated Trial of Org 10172 in Acute Stroke Treatment classifications to address potential differences in thrombus pathogenesis.

Results

Amounts of leukocytes (p = 0.133) and neutrophils (p = 0.56) were similar between AIS and AMI thrombi. Monocytes (p = 0.0052), eosinophils (p < 0.0001), B cells (p < 0.0001), and T cells (p < 0.0001) were more abundant in stroke compared with AMI thrombi. NETs were present in 100% of patients with AIS and 20.8% of patients with AMI. Their abundance in thrombi was associated with poor outcome scores in patients with AIS and with reduced ejection fraction in patients with AMI.

Conclusion

In our detailed histologic analysis of arterial thrombi, thrombus composition and especially abundance of leukocyte subsets differed between patients with AIS and AMI. The presence and amount of NETs were associated with patients' outcome after AIS and AMI, supporting a critical impact of NETs on thrombus stability in both conditions.

We conducted a cross-sectional analysis of ARIC participants with data on kidney measures and VWMRI in 2011 to 2013. The main outcomes were presence of intracranial plaques and luminal stenosis. Multivariable models were adjusted for demographics, cardiovascular risk factors, and use of antithrombotic medications.

In community-dwelling older adults, reduced kidney function or elevated kidney damage was associated with ICAD measured by VWMRI. This finding may help to better identify a population at high risk for ICAD.

Disease-modifying treatments (DMTs) are the gold standard for slowing disability progression in multiple sclerosis (MS), but their effects on cognitive impairment, a key symptom of the disease, are mostly unknown. We conducted a systematic review and meta-analysis to evaluate the differential effects of DMTs on cognitive test performance in relapsing-remitting MS (RRMS).

Methods

PubMed, Scopus, and Cochrane Library were searched for studies reporting longitudinal cognitive performance data related to all major DMTs. The standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used as the main effect size measure.

DMTs are effective in improving cognitive test performance in RRMS, but a treatment escalation mainly to amend cognition is not supported by the current evidence. Given the multitude of DMTs and their widespread use, the available data regarding differential treatment effects on cognitive impairment are remarkably scant. Clinical drug trials that use more extensive cognitive outcome measures are urgently needed.

RSMS score showed a similar pattern in mutation carriers and noncarriers, with significant drops at each stage of progression from asymptomatic to very mild, mild, moderate, and severe disease (F4,48 = 140.10, p < 0.001) and a significant slope of decline over time in patients with bvFTD (p = 0.004, 95% confidence interval [CI] –1.90 to –0.23). More rapid declines on the RSMS corresponded to faster gray matter atrophy predominantly in the salience network (SN), and RSMS score progression best predicted thalamic volume in very mild and mild disease stages of bvFTD. Higher RSMS score predicted more caregiver burden (p < 0.001, 95% CI –0.30 to –0.11).

Conclusions

The RSMS is sensitive to progression of both socioemotional symptoms and SN atrophy in patients with bvFTD and corresponds directly to caregiver burden. The RSMS may be useful in both neurologic practice and clinical trials aiming to treat behavioral symptoms of patients with bvFTD.

]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009451hwp:master-id:neurology;WNL.0000000000009451American Academy of Neurology2020-06-02ARTICLE9422e2384e2395
hw_mjid:neurology;94/22/e2384
http://n.neurology.org/cgi/content/short/94/22/e2396?rss=1
A healthy 84-year-old woman of Chinese ethnicity presented with multiple separate episodes of focal neurologic deficits (right-sided weakness with aphasia, as well as left-sided weakness) over 2 days, in the context of 3 months of subacute cognitive decline. She had been well leading up to this presentation. CT angiogram showed multifocal constriction of the middle cerebral arteries and bilateral M3 occlusions. Posterior circulation vessels were unremarkable. Cerebral MRI with gadolinium showed multiple foci of restricted diffusion in the bilateral frontal and parietal lobes and diffuse T2/fluid-attenuated inversion recovery changes without abnormal enhancement, consistent with infarction of varying ages (figure 1, A). She was started on low-dose acetylsalicylic acid and deep vein thrombosis prophylaxis and admitted to the hospital.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009534hwp:master-id:neurology;WNL.0000000000009534American Academy of Neurology2020-06-02RESIDENT &amp;amp; FELLOW SECTION9422e2396e2401
hw_mjid:neurology;94/22/e2396
http://n.neurology.org/cgi/content/short/94/22/e2402?rss=1
A 50-year-old woman underwent embolization of an anterior communicating artery aneurysm, via the left internal carotid artery, using the penumbra SMART coil system. Follow-up CT angiography at 16 months revealed a 2-mm hyperdense lesion in the left parietal lobe (figure 1). MRI confirmed multiple punctate enhancing foci with surrounding edema favored to represent nonischemic cerebral enhancing (NICE) lesions (figure 2). NICE lesions are rare complications of coil embolization putatively associated with nickel allergy or coil emboli,1 although the SMART coil system is platinum based. The patient remained asymptomatic and further workup was withheld. Follow-up MRI at 1.5 months showed resolution.
]]>2020-06-01T12:45:28-07:00info:doi/10.1212/WNL.0000000000009537hwp:master-id:neurology;WNL.0000000000009537American Academy of Neurology2020-06-02RESIDENT &amp;amp; FELLOW SECTION9422e2402e2403
hw_mjid:neurology;94/22/e2402
http://n.neurology.org/cgi/content/short/94/21/901?rss=1
2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009503hwp:resource-id:neurology;94/21/901American Academy of Neurology2020-05-26IN FOCUS9421901902
hw_mjid:neurology;94/21/901
http://n.neurology.org/cgi/content/short/94/21/903?rss=1
The coronavirus disease of 2019, or COVID-19, changed the world within a matter of weeks. The primary action to constrain the spread of the virus is social isolation. Given this public health principle, and the shortage of personal protective equipment during the global pandemic, all health care stakeholders need to reconsider the indications for face-to-face health care encounters in providing patient care. Which encounters are imperative and which ones can be switched to non–face-to-face care? What changes in laws, regulations, payment policies, and workflow are needed to enable this transition?1–3
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009494hwp:master-id:neurology;WNL.0000000000009494American Academy of Neurology2020-05-26SPECIAL EDITORIALS9421903904
hw_mjid:neurology;94/21/903
http://n.neurology.org/cgi/content/short/94/21/905?rss=1
Italy is facing its fifth week of crisis due to the Coronavirus disease (COVID-19) outbreak, with affected patients and deaths near to 70,000 and 6,000, respectively,1 numbers that are increasing every day. Whether government imposition of quarantines, travel bans, and lockdown throughout the country will have effect in the next weeks in limiting the spreading of this disease has still to be seen. Meanwhile, a great spirit of sacrifice is required to health care personnel, and authorities have to manage resource allocation to rapidly increase the number of intensive care beds to assist patients with COVID-19.2 Although operating rooms and a number of wards have been turned into dedicated intensive units, beds and resources are hardly sufficient to satisfy the needs of so many simultaneously critically ill patients.3,4 Notably, among infected people, about 10% are health workers, and their number is increasing, also due to the scarcity of efficacious protective measures.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009508hwp:master-id:neurology;WNL.0000000000009508American Academy of Neurology2020-05-26SPECIAL EDITORIALS9421905906
hw_mjid:neurology;94/21/905
http://n.neurology.org/cgi/content/short/94/21/907?rss=1
Wilson disease (WD) is a monogenic, autosomal recessively inherited copper storage disorder due to biallelic mutations in the copper-transporting protein ATP7B. The 2 most common presentations are the hepatic presentation (typically in childhood) and the neurologic presentation (typically in early adulthood).1 However, later onset, especially for patients with the neurologic presentation, is well recognized, with some patients presenting in their 70s.2 Recent genetic studies suggest that the previously accepted and widely published prevalence figure of 1:30,000 may be an underestimate, but this is still a matter of debate.3,4 The observation of Kayser-Fleischer (KFR) rings can quickly establish the clinical diagnosis in patients with the neurology textbook presentation of wing-beating tremor combined with dysarthria. However, many other patients will present with a more complex movement disorder.5
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009476hwp:master-id:neurology;WNL.0000000000009476American Academy of Neurology2020-05-26EDITORIALS9421907908
hw_mjid:neurology;94/21/907
http://n.neurology.org/cgi/content/short/94/21/909?rss=1
Cerebral small vessel disease (SVD) includes pathology of the brain's small arteries, arterioles, capillaries, venules, and veins.1 Key risk factors for SVD include age and cardiovascular risk factors,2,3 although vascular risk does not fully account for SVD, pointing to its multifactorial nature and, as of yet, unclear underlying mechanism. SVD is associated with an increased risk of stroke, dementia, and mortality.4 Early detection and prevention of SVD could have a large effect at the population level, given the strong clinical relevance and the seriousness of the potential consequences, but the extended latency period of SVD and difficulty measuring the structure and function of the vessels has limited progress in this area. Traditional MRI-based markers of SVD include white matter hyperintensities (WMHs) of presumed vascular origin, silent brain infarcts or lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (PVSs). Yet, these neuroimaging markers primarily represent distal, parenchymal consequences of vessel pathology rather than the vessel pathology itself. Furthermore, given inconsistent associations of specific SVD markers with clinical features such as cognition,5,6 these traditional markers do not capture fully the relationship of pathology of the small vessels with important outcomes.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009477hwp:master-id:neurology;WNL.0000000000009477American Academy of Neurology2020-05-26EDITORIALS9421909910
hw_mjid:neurology;94/21/909
http://n.neurology.org/cgi/content/short/94/21/919?rss=1
The April 30, 2019, podcast interview highlighted a mouse model of anti-NMDA receptor post–herpes simplex encephalitis. What's Trending discusses ataxias.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009487hwp:resource-id:neurology;94/21/919American Academy of Neurology2020-05-26WHAT'S HAPPENING9421919919
hw_mjid:neurology;94/21/919
http://n.neurology.org/cgi/content/short/94/21/920?rss=1
Articles appearing in the June 2020 issue
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009505hwp:resource-id:neurology;94/21/920American Academy of Neurology2020-05-26WHAT'S HAPPENING9421920920
hw_mjid:neurology;94/21/920
http://n.neurology.org/cgi/content/short/94/21/921?rss=1
Gretchen Birbeck, MD, MPH
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009482hwp:resource-id:neurology;94/21/921American Academy of Neurology2020-05-26WHAT'S HAPPENING9421921921
hw_mjid:neurology;94/21/921
http://n.neurology.org/cgi/content/short/94/21/922?rss=1
Objectives

Atherothrombosis in the carotid arteries is a main cause of ischemic stroke and may depend on plaque propensity to complicate with rupture or erosion, in turn related to vulnerability features amenable to in vivo imaging. This would provide an opportunity for risk stratification and—potentially—local treatment of more vulnerable plaques. We here review current information on this topic.

Methods

We systematically reviewed the literature for concepts derived from pathophysiologic, histopathologic, and clinical studies on imaging techniques attempting at identifying vulnerable carotid lesions.

Results

Ultrasound, MRI, CT, and nuclear medicine–based techniques, alone or with multimodality approaches, all have a link to pathophysiology and describe different—potentially complementary—aspects of lesions prone to complications. There is also, however, a true paucity of head-to-head comparisons of such techniques for practical implementation of a thorough and cost-effective diagnostic strategy based on evaluation of outcomes. Especially in asymptomatic patients, major international societies leave wide margins of indecision in the advice to techniques guiding interventions to prevent atherothrombotic stroke.

Conclusions

To improve practical management of such patients—in addition to the patient's vulnerability for systemic reasons—a more precise identification of the vulnerable plaque is needed. A better definition of the diagnostic yield of each imaging approach in comparison with the others should be pursued for a cost-effective translation of the single techniques. Practical translation to guide future clinical practice should be based on improved knowledge of the specific pathophysiologic correlates and on a comparative modality approach, linked to subsequent stroke outcomes.

]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009480hwp:master-id:neurology;WNL.0000000000009480American Academy of Neurology2020-05-26VIEWS &amp;amp; REVIEWS9421922932
hw_mjid:neurology;94/21/922
http://n.neurology.org/cgi/content/short/94/21/933?rss=1
A 5-month-old patient was first evaluated for a hypotonic hyporeflexic syndrome; over years, the phenotype evolved to involve ataxia, developmental delay, and coarse facies. Brain MRI showed abnormal configuration of cerebellar folia, rearranged in radial shape (figure). Whole exome sequencing analysis revealed the c.512 G>A (p.G171D) de novo mutation in EBF3. EBF3 gene function is crucial for neuronal migration during corticogenesis.1 Cerebellar foliation is complex: folia sprout from anchoring centers,2 whose distribution and number determine the shape of lobules and fissures; EBF3 mutations may disrupt this process, thus causing the peculiar cerebellar lobule appearance seen here.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009486hwp:master-id:neurology;WNL.0000000000009486American Academy of Neurology2020-05-26NEUROIMAGES9421933935
hw_mjid:neurology;94/21/933
http://n.neurology.org/cgi/content/short/94/21/936?rss=1
With much thanks, appreciation, and fondness, the Resident & Fellow Section (RFS) of Neurology thanks Dr. John Millichap, who stepped down as Section Editor in April 2020. Dr. Millichap initially served as an editorial board member for the RFS, then Deputy Editor from 2011–2015, and Section Editor until May 2020. Under his tremendous leadership, the RFS has grown from 507 submissions in 2015 to over 800 in 2019. His forethought and vision led to new subsections, including Journal Club, Global & Community Health, and Emerging Subspecialties in Neurology. He was instrumental in the publication of the section's second e-book in child neurology and expanded the editorial board to include international residents and fellows. He has contributed to the professional development of countless trainees, and on behalf of them all, we send our sincerest thanks and gratitude to Dr. Millichap. He leaves big shoes to fill for Dr. Roy Strowd, who stepped in as Section Editor in May.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009506hwp:resource-id:neurology;94/21/936American Academy of Neurology2020-05-26RESIDENT &amp;amp; FELLOW ROUNDS9421936938
hw_mjid:neurology;94/21/936
http://n.neurology.org/cgi/content/short/94/21/939?rss=1
A 10-month-old girl presented with global developmental delay, epileptic spasms, and easy bruisability. She was fourth-born of third-degree consanguineous parents with 3 healthy siblings. The perinatal period was uneventful. Examination revealed microcephaly, central hypotonia, acrocyanosis, mottled skin, and petechiae over extremities (figure 1). Neuroimaging revealed peculiar findings (figure 2). EEG revealed modified hypsarrhythmia (figure 3). Epileptic spasms resolved with oral prednisolone therapy (given at 3 mg/kg/d for 2 weeks followed by tapering over 6 weeks). She had elevated C4-acylcarnitines on tandem mass spectrometry (TMS) and urinary ethylmalonic acid on urine gas chromatography mass spectrometry (GCMS). The diagnosis of ethylmalonic encephalopathy (EE) was confirmed genetically (c.487C > T; p.Arg163Trp homozygous variation in ETHE1). She was initiated on N-acetyl cysteine, metronidazole, and mitochondrial cocktail but died of an acute crisis at 14 months of age.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009479hwp:master-id:neurology;WNL.0000000000009479American Academy of Neurology2020-05-26RESIDENT &amp;amp; FELLOW SECTION9421939942
hw_mjid:neurology;94/21/939
http://n.neurology.org/cgi/content/short/94/21/943?rss=1
In their article, Narendra et al. reported the case of a 35-year-old man with novel compound heterozygous DJ1 mutations who presented with early-onset Parkinson disease (PD) and was found to have autonomic peripheral synucleinopathy and impaired olfaction. They proposed that the clinical triad of early-onset PD, cataracts, and sensorineural hearing loss seen in this patient may be specific for DJ1. In response, Drs. Namnah et al. referenced 2 other published cases that reported a similar association and report another patient of Iranian-Jewish ancestry with young-onset cataracts and PD with DJ1 mutations, suggesting that young-onset cataracts in PD should direct clinicians to DJ1 testing. Responding to this comment, Narendra et al. note that the patient reported by Namnah et al.—besides substantiating their conclusion—also had both lower and upper motor neuron signs—another atypical PD feature seen in some DJ1 patients. They also note that 2 of the reported patients with Iranian-Jewish ancestry shared a mutation with another reported family of Iranian-Jewish descent, indicating a founder effect in this population. This exchange highlights the enduring importance of meticulously characterized case reports in modern neurology to strengthen genotype-phenotype correlations, particularly in relatively rare genetic diseases.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009488hwp:resource-id:neurology;94/21/943American Academy of Neurology2020-05-26DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9421943943
hw_mjid:neurology;94/21/943
http://n.neurology.org/cgi/content/short/94/21/943-a?rss=1
We read with interest the article by Narendra et al.1 that described a patient with Parkinson disease (PD) and young-onset bilateral cataracts associated with compound heterozygous DJ1 (PARK7) mutations. This observation confirms a suspected association between young-onset cataracts and DJ1-PD that was previously reported in 2 other cases.2,3 We report here an additional case that further strengthens this genotype-phenotype correlation and indicates that DJ1 mutations should be suspected in PD cases with young-onset cataracts.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009495hwp:resource-id:neurology;94/21/943-aAmerican Academy of Neurology2020-05-26DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9421943944
hw_mjid:neurology;94/21/943-a
http://n.neurology.org/cgi/content/short/94/21/944?rss=1
We welcome the additional confirmed DJ1/PARK7 case and another probable case reported by Namnah et al. in their comment on our article.1 They further substantiate the occurrence of early cataracts in DJ1/PARK7 present in 5/35 (14.3%) cases. The case reported by Namnah et al. also highlights lower and upper motor signs in DJ1/PARK7 patients. Lower motor neuron signs are now documented in 8/35 (22.9%) cases and upper motor neuron signs in 10/35 (28.6%) cases. Finally, it is notable that the 2 patients of Iranian-Jewish ancestry described by Namnah et al. carry a mutation recently identified in another family of Iranian-Jewish descent (GRCh37:NM_007262.4:c.80dupG, p[Ile31Aspfs*2]), consistent with a founder effect in this population.2
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009502hwp:resource-id:neurology;94/21/944American Academy of Neurology2020-05-26DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9421944944
hw_mjid:neurology;94/21/944
http://n.neurology.org/cgi/content/short/94/21/944-a?rss=1
Rocha et al. developed a discriminatory score in a cohort of 30 patients with reversible cerebral vasoconstriction syndrome (RCVS) and 80 patients with non-RCVS arteriopathy, and they validated it in a separate cohort of RCVS and its mimic, primary angiitis of the CNS (PACNS). They found that a score that evaluated for recurrent/single thunderclap headache, carotid artery involvement (less likely with RCVS), vasoconstrictive trigger, female sex, and subarachnoid hemorrhage could accurately distinguish RCVS from other intracranial arteriopathies. In response, Drs. Yuan and Hu highlight some limitations of the study, including the use of retrospective study data, limited sample size, inclusion of 2 variables relying on the patient's subjective recall (vasoconstrictive trigger and thunderclap headache), lack of a gold standard, and the need to validate the score's ability to distinguish RCVS from arteriopathies other than PACNS. They propose using additional readily available clinical variables and imaging markers such as vessel wall imaging and transcranial color-coded sonography to further refine and validate the score. Responding to these comments, Drs. Singhal and Rocha note that several of these limitations were acknowledged in the article. They counter that advanced vessel wall imaging or biomarker studies are unlikely to improve the near-perfect performance of RCVS2 scores >5 or <2 in their study but may have some utility in patients with intermediate scores. They argue that patients' recall of thunderclap headache is likely to be reliable, given the uniqueness of the experience, whereas patients may underreport vasoconstrictive triggers such as illicit drugs and over-the-counter medications. This exchange underscores the challenges and disagreements that may be encountered when developing and refining clinical scores for neurologic conditions.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009499hwp:resource-id:neurology;94/21/944-aAmerican Academy of Neurology2020-05-26DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9421944945
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http://n.neurology.org/cgi/content/short/94/21/945?rss=1
We read with interest the article by Rocha et al.,1 who developed a new diagnostic tool to distinguish reversible cerebral vasoconstriction syndrome (RCVS) from other intracranial arteriopathies. The RCVS2 score performed perfect specificity and sensitivity for the differential diagnosis between RCVS and non-RCVS arteriopathy at admission. However, there were some issues, which should be raised. First, as a retrospective study, there was a limited sample size in a stroke center (30 RCVS vs 80 non-RCVS). Prospective studies with larger samples from multiple centers in the other sites of the United States or the other countries are urgently needed to confirm. Second, besides the objective 3 variables of RCVS2 score (carotid artery involvement, sex, and subarachnoid hemorrhage), both the thunderclap headache and vasoconstrictive trigger were derived from the patients' subjective complaints and lack of golden standard to assess, which may lead to higher false positivity. Third, using the data from a published cohort,2 this study only validated to distinguish RCVS from primary angiitis of the CNS, not including all the non-RCVS arteriopathies just as mentioned in the derivation cohort, such as moyamoya disease, intracranial atherosclerosis, secondary vasculitis, and radiation-induced arteriopathy. As a quite novel tool for accurate differential diagnosis of RCVS and non-RCVS, more available clinical variables, imaging features (such as vascular wall imaging3 and transcranial color-coded sonography4), and other biomarkers are warranted to confirm such findings.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009501hwp:resource-id:neurology;94/21/945American Academy of Neurology2020-05-26DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9421945946
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http://n.neurology.org/cgi/content/short/94/21/946?rss=1
We thank Drs. Yuan and Hu for their comments. We already acknowledged the sample size limitation, the need for external validation, the need to assess RCVS2 score performance in distinguishing RCVS from arteriopathies other than primary angiitis of the CNS, and that advanced vessel wall imaging or biomarker studies are unlikely to improve on the near-perfect performance of RCVS2 scores >5 or <2 (but may have some utility in patients with intermediate scores 3 or 4).1 With regard to a possible high false-positive rate for thunderclap headache and vasoconstrictive triggers, we believe that this is unlikely. Thunderclap headache is a unique and unforgettable symptom, so documentation is usually accurate. Patients tend to underreport vasoconstrictive triggers such as illicit drugs and over-the-counter medications, so a high false-negative rate is more likely.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009500hwp:resource-id:neurology;94/21/946American Academy of Neurology2020-05-26DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9421946946
hw_mjid:neurology;94/21/946
http://n.neurology.org/cgi/content/short/94/21/e2189?rss=1
Objective

To evaluate the effect of liver transplantation (LT) in patients with Wilson disease (WD) with severe neurologic worsening resistant to active chelation.

Methods

French patients with WD who underwent LT for pure neurologic indication were retrospectively studied. Before LT and at the last follow-up, neurologic impairment was evaluated with the Unified Wilson's Disease Rating Scale (UWDRS) score, disability with the modified Rankin Scale (mRS) score, and hepatic function with the Model for End-stage Liver Disease score, together with the presence of a Kayser-Fleischer ring (KFR), brain MRI scores, and copper balance. The survival rate and disability at the last follow-up were the coprimary outcomes; evolution of KFR and brain MRI were the secondary outcomes. Prognosis factors were further assessed.

Results

Eighteen patients had LT. All were highly dependent before LT (median mRS score 5). Neurologic symptoms were severe (median UWDRS score 105), dominated by dystonia and parkinsonism. The cumulated survival rate was 88.8% at 1 year and 72.2% at 3 and 5 years. At the last follow-up, 14 patients were alive. Their mRS and UWDRS scores improved (p < 0.0001 and p = 0.0003). Eight patients had a major improvement (78% decrease of the UWDRS score), 4 a moderate one (41% decrease), and 2 a stable status. KFR and brain MRI scores improved (p = 0.0007). Severe sepsis (p = 0.011) and intensive care unit admission (p = 0.001) before LT were significantly associated with death.

Conclusions

LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk.

To evaluate the effectiveness of yoga as an adjuvant to conventional medical management on clinical outcomes in patients with migraine.

Methods

CONTAIN was a prospective, randomized, open-label superiority trial with blinded endpoint assessment carried out at a single tertiary care academic hospital in New Delhi, India. Patients enrolled were aged 18–50 years with a diagnosis of episodic migraine and were randomized into medical and yoga groups (1:1). Randomization was computer-generated with a variable block size and concealed. A predesigned yoga intervention was given for 3 months. Outcomes were recorded by a blinded assessor. The primary endpoint was a decrease in headache frequency, headache intensity, and Headache Impact Test (HIT)–6 score. Secondary outcomes included change in Migraine Disability Assessment (MIDAS) score, pill count, and proportion of headache free patients.

To determine whether patients with cluster headache have more sickness absence and disability pension days compared to matched references and possible associations with sociodemographic characteristics.

Methods

We performed a registry study of all patients who had received specialized health care for cluster headache (ICD-10 code G44.0) aged 16–64 years and living in Sweden in 2010 (n = 3,240; 34% women) and matched references from the total population (n = 16,200) regarding their sickness absence and disability pension days in 2010.

Results

Mean number of sickness absence days in 2010 was 16.13 (95% confidence interval, 14.05–18.20) among patients with cluster headache and 6.54 (5.97–7.11) among references. When combining sickness absence and disability pension days, patients with cluster headache had 63.15 (58.84–67.45) days, references 34.08 (32.59–35.57) days. Among patients, women had twice as many sickness absence days than men: 23.71 (19.36–28.06) vs 12.41 (10.19–14.63). When adding disability pension days, those numbers were 83.71 (75.57–91.84) vs 52.56 (47.62–57.51). Patients with cluster headache had significantly more sickness absence days in all ages compared to the reference group. Patients with elementary education had more sickness absence/disability pension days (85.88 [75.34–96.42]) compared to those with high school (64.89 [58.82–70.97]) and college/university (41.42 [34.70–48.15]) education.

Conclusion

This nationwide study shows that patients with cluster headache have significantly more sickness absence and disability pension days compared to matched references. Furthermore, among patients, women had more sickness absence and disability pension days than men.

To assess the dose-response of daridorexant, a new dual orexin receptor antagonist, on wake after sleep onset (WASO).

Methods

Elderly (≥65 years) participants (n = 58) with insomnia were randomly allocated (Latin square design) to receive 5 treatments (5, 10, 25, and 50 mg daridorexant and placebo) during 5 treatment periods, each consisting of 2 treatment nights followed by a 5- to 12-day washout period. Main efficacy endpoints were the absolute change from baseline in WASO (primary) and latency to persistent sleep (LPS; secondary) to days 1 and 2 (mean of 2 treatment nights assessed by polysomnography) in each period. Safety and tolerability were also assessed.

Results

Of 58 participants included, 67% were female, and the median age was 69 years (range 65–85 years). WASO and LPS were dose-dependently reduced from baseline to days 1 and 2 after daridorexant administration (multiple comparison procedure modeling, p < 0.0001 and p = 0.004, respectively); reductions were statistically significant for doses ≥10 mg compared with placebo (WASO: –32.0, –45.1, –61.4 minutes; LPS: –44.9, –43.8, –45.4 minutes for 10, 25, and 50 mg, respectively, p ≤ 0.025). Treatment-emergent adverse events were similar for daridorexant and placebo; the most frequent were fatigue, nasopharyngitis, gait disturbance, and headache (≤7% in any group).

Conclusions

Daridorexant was well tolerated. Dose-dependent improvements in WASO and LPS were statistically significant (dose range 10–50 mg) in elderly people with insomnia disorder.

ClinicalTrials.gov identifier:

NCT02841709.

Classification of evidence

This study provides Class I evidence that, for elderly people with insomnia, daridorexant reduced WASO.

To compare different β-amyloid (Aβ), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies.

Methods

A total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aβ42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation.

Results

Among CU participants, A–T–(N)– or A+T–(N)– variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures.

Conclusions

Our findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.

To test the hypothesis that aerobic exercise is associated with improvements in cognition and cerebrovascular regulation, we enrolled 206 healthy low-active middle-aged and older adults (mean ± SD age 65.9 ± 6.4 years) in a supervised 6-month aerobic exercise intervention and assessed them before and after the intervention.

Methods

The study is a quasi-experimental single group pre/postintervention study. Neuropsychological tests were used to assess cognition before and after the intervention. Transcranial Doppler ultrasound was used to measure cerebral blood flow velocity. Cerebrovascular regulation was assessed at rest, during euoxic hypercapnia, and in response to submaximal exercise. Multiple linear regression was used to examine the association between changes in cognition and changes in cerebrovascular function.

The 6-month aerobic exercise intervention was associated with improvements in some cognitive domains and cerebrovascular regulation. Secondary analyses showed a novel association between changes in cognition and changes in cerebrovascular regulation during euoxic hypercapnia and in response to submaximal exercise.

To investigate cerebrovascular reactivity (CVR), blood flow, vascular and CSF pulsatility, and their independent relationship with cerebral small vessel disease (SVD) features in patients with minor ischemic stroke and MRI evidence of SVD.

Part 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.

Results

Twelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ~16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%–4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.

This study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.

]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009233hwp:master-id:neurology;WNL.0000000000009233American Academy of Neurology2020-05-26ARTICLE9421e2270e2282
hw_mjid:neurology;94/21/e2270
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A 17-year-old African Brazilian woman presented with a 1-year history of progressive ataxia, dysarthria, and decreased visual acuity. Family history was remarkable for multiple relatives with similar motor symptoms but no visual complaints. Examination showed upward gaze palsy, dysarthria, ataxia, and increased tone and reflexes. Fundoscopic examination and subsequent optical coherence tomography revealed bilateral atrophic maculopathy (figures 1 and 2). Genetic testing confirmed the diagnosis of spinocerebellar ataxia type 3 (SCA3) by revealing abnormal CAG repeats in the ATXN3 gene—the pathologic allele had 68 repeats and the normal allele 14 repeats.
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009484hwp:master-id:neurology;WNL.0000000000009484American Academy of Neurology2020-05-26RESIDENT &amp;amp; FELLOW SECTION9421e2283e2284
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A 28-year-old man had experienced binocular diplopia for the last 2 months. Around the same time, he noticed mostly nocturnal polyuria and polydipsia and eventually was diagnosed with diabetes insipidus. Extraocular motility testing demonstrated jerky convergence movements on an attempted upgaze and mild lid retraction (video 1). Urgent MRI of the brain revealed a large mass in the dorsal midbrain region, which was also compressing the hypothalamus (figure). The lesion was biopsied and a diagnosis of primary intracranial germinoma arising from pineal tissue was made. Treatment with low-dose radiotherapy commenced. Characteristic clinical features of convergence retraction nystagmus in this case allowed rapid localization of the lesion, its diagnosis, and eventually treatment.1
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009481hwp:master-id:neurology;WNL.0000000000009481American Academy of Neurology2020-05-26RESIDENT &amp;amp; FELLOW SECTION9421e2285e2286
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http://n.neurology.org/cgi/content/short/94/21/e2287?rss=1
In this issue of Neurology®, the authors of this study determined whether daridorexant, a new sleep medication, was safe and effective in treating insomnia for adults >65 years of age.1 Insomnia is difficulty falling asleep or staying asleep that may interfere with daytime functioning, including an increased risk for falls, mood disorders such as depression, and decreased quality of life.2,3 It can be seen in about half of older adults. There are treatments, but commonly used medications for insomnia in older adults can increase the risk of thinking problems and falls.2,3
]]>2020-05-25T12:45:27-07:00info:doi/10.1212/WNL.0000000000009489hwp:resource-id:neurology;94/21/e2287American Academy of Neurology2020-05-26PATIENT PAGES9421e2287e2289
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http://n.neurology.org/cgi/content/short/94/20/853?rss=1
2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009453hwp:resource-id:neurology;94/20/853American Academy of Neurology2020-05-19IN FOCUS9420853854
hw_mjid:neurology;94/20/853
http://n.neurology.org/cgi/content/short/94/20/855?rss=1
Neurologists are used to uncertainty—diagnoses are frequently challenging, too often there are limited treatment options, and unpredictable prognoses are our bread and butter. When colleagues struggle to communicate bad news, they regularly turn to us. We practice staying steady and calm amidst our patients' fears, confusion, suffering, and anxiety. We listen, perform detailed examinations, and do our best to provide helpful insights. This emphasis on listening and thoughtful problem solving is the core of our art and should be front and center as we partner with colleagues to face an unprecedented set of challenges related to the Coronavirus Disease 2019 (COVID-19) pandemic.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009496hwp:master-id:neurology;WNL.0000000000009496American Academy of Neurology2020-05-19SPECIAL EDITORIALS9420855857
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Dementia with Lewy bodies (DLB) is a relatively new diagnostic entity compared with Parkinson disease (PD) and associated dementia, with DLB consensus criteria first published in 1996.1 In the initial and subsequent DLB consensus criteria, a key feature separating DLB from PD dementia (PDD) has been the order of motor vs cognitive symptoms. In PDD, individuals have a PD diagnosis first based on motor features and subsequently develop dementia. In DLB, dementia is present earlier on. To operationalize criteria for practical use, DLB diagnostic criteria suggested the 1-year rule, where DLB should be diagnosed if dementia emerges before or within 1 year of parkinsonian motor symptoms. This was consistent with commonly used PD criteria, in which early dementia was an exclusion criterion2 and PDD was diagnosed in the context of established PD.3 Diagnostic boundaries became more blurred and confusing in 2015, when the Movement Disorder Society published new PD criteria removing early dementia as an exclusion criterion, and subsuming individuals with DLB with parkinsonism into PD, with an optional DLB subtype designation.4 This led to debates regarding whether DLB and PDD represent the same disease, distinct entities, or conditions on the same spectrum.5,6 Discussions on this topic continue, and updated DLB criteria maintaining the 1-year rule were published in 2017,7 while acknowledging that the 1-year marker was a largely arbitrary placeholder for operational use.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009433hwp:master-id:neurology;WNL.0000000000009433American Academy of Neurology2020-05-19EDITORIALS9420858859
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Parkinson disease (PD) is a progressive neurodegenerative disorder of the motor system that affects 6.2 million people globally.1 The exact pathogenic mechanism underlying PD remains unclear. Although the current drugs for PD can relieve disease symptoms to some extent, the efficacy duration is limited, and it is hard to cure, halt, or reverse the disease.2 Therefore, the identification of modifiable risk factors is imperative for the prevention of PD.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009431hwp:master-id:neurology;WNL.0000000000009431American Academy of Neurology2020-05-19EDITORIALS9420860861
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http://n.neurology.org/cgi/content/short/94/20/862?rss=1
Surveys of primary care physicians indicate that seizures are 1 of the top 5 reasons to obtain an e-consult with a neurologist, with diagnostic tests such as EEG among the top reasons to request reevaluation,1 especially because EEG is an essential, well-established diagnostic tool for evaluating and managing people with epilepsy.2 Visual interpretation of EEG recordings has high specificity for an epilepsy diagnosis based on the presence of abnormal epileptiform discharges (EDs), but only moderate and variable interrater reliability3,4 for correct interpretation. Pitfalls for correct ED identification include overinterpretation of the EEG and can lead to misdiagnosis of people who do not have epilepsy.5 The initial criteria adopted by the International Federation of Clinical Neurophysiology (IFCN) to distinguish EDs are not sufficient to separate pathologic EDs from normal features of the EEG.6 Importantly, new definitions of epilepsy now include a single seizure, when it is associated with EDs. This underscores the critical importance of EEG following an initial seizure. In turn, correctly interpreted EEG results may prompt treatment with antiseizure medication that may limit seizure recurrence.7
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009432hwp:master-id:neurology;WNL.0000000000009432American Academy of Neurology2020-05-19EDITORIALS9420862863
hw_mjid:neurology;94/20/862
http://n.neurology.org/cgi/content/short/94/20/874?rss=1
Papers appearing in the June 2019 issue
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009456hwp:resource-id:neurology;94/20/874American Academy of Neurology2020-05-19WHAT'S HAPPENING9420874874
hw_mjid:neurology;94/20/874
http://n.neurology.org/cgi/content/short/94/20/875?rss=1
Articles appearing in the September 2019 issue
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009442hwp:resource-id:neurology;94/20/875American Academy of Neurology2020-05-19WHAT'S HAPPENING9420875875
hw_mjid:neurology;94/20/875
http://n.neurology.org/cgi/content/short/94/20/876?rss=1
Objective

To update the 2016 American Academy of Neurology (AAN) practice advisory for patients with stroke and patent foramen ovale (PFO).

Methods

The guideline panel followed the AAN 2017 guideline development process to systematically review studies published through December 2017 and formulate recommendations.

Major recommendations

In patients being considered for PFO closure, clinicians should ensure that an appropriately thorough evaluation has been performed to rule out alternative mechanisms of stroke (level B). In patients with a higher risk alternative mechanism of stroke identified, clinicians should not routinely recommend PFO closure (level B). Clinicians should counsel patients that having a PFO is common; that it occurs in about 1 in 4 adults in the general population; that it is difficult to determine with certainty whether their PFO caused their stroke; and that PFO closure probably reduces recurrent stroke risk in select patients (level B). In patients younger than 60 years with a PFO and embolic-appearing infarct and no other mechanism of stroke identified, clinicians may recommend closure following a discussion of potential benefits (absolute recurrent stroke risk reduction of 3.4% at 5 years) and risks (periprocedural complication rate of 3.9% and increased absolute rate of non-periprocedural atrial fibrillation of 0.33% per year) (level C). In patients who opt to receive medical therapy alone without PFO closure, clinicians may recommend an antiplatelet medication such as aspirin or anticoagulation (level C).

]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009443hwp:master-id:neurology;WNL.0000000000009443American Academy of Neurology2020-05-19LEVEL OF RECOMMENDATION9420876885
hw_mjid:neurology;94/20/876
http://n.neurology.org/cgi/content/short/94/20/886?rss=1
Beginning in December 2019, a novel coronavirus, SARS-CoV-2 (COVID-19), began spreading rapidly throughout China and now is a global pandemic, with cases reported in over 192 countries and territories worldwide. Clinically, COVID-19 ranges from a mild, self-limiting respiratory illness to severe progressive pneumonia and multiorgan failure. The first COVID-19 case was reported at the beginning of March in New York City (NYC), and now just 3 weeks later, NYC and its suburbs have over 5% of global cases. Worldwide, there is a rapid increase in the number of cases daily, including the number of patients requiring hospitalization and intensive care support.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009519hwp:master-id:neurology;WNL.0000000000009519American Academy of Neurology2020-05-19CONTEMPORARY ISSUES9420886891
hw_mjid:neurology;94/20/886
http://n.neurology.org/cgi/content/short/94/20/892?rss=1
A previously healthy 10-year-old girl of Croatian descent presented to the pediatric neurology clinic with an abnormal gait. She first noted symptoms 1.5 years prior to presentation, which included flexion–inversion posturing of her left foot while playing soccer. She would drag her left foot, leading to excessive falling. Her family noted that she did not seem to have much difficulty ambulating at the beginning of the day and they did not notice any abnormal posturing of the foot when she woke up in the morning. However, by the evening, they noted her left foot, and occasionally her right foot, would develop a flexion–inversion posture. Her symptoms seemed to be worse when she was tired or after activity. She had previously been evaluated by 2 orthopedic surgeons and a pediatric neurologist and was most recently seen in an emergency department for this problem, with no diagnosis being provided. Workup included a normal lumbar spine MRI and X-rays of both legs.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009040hwp:master-id:neurology;WNL.0000000000009040American Academy of Neurology2020-05-19RESIDENT &amp;amp; FELLOW SECTION9420892895
hw_mjid:neurology;94/20/892
http://n.neurology.org/cgi/content/short/94/20/896?rss=1
Using data from the Nationwide Inpatient Sample, Drs. Faigle et al. compared the incidence rates of carotid intervention between hospitals that serve a predominantly white population (<40% racial/ethnic minority prevalence) against hospitals that serve a predominantly minority population (≥40% minority). Even after adjusting for individual self-reported race/ethnicity, insurance provider, hospital characteristics, and patient comorbidities, the investigators observed a significantly lower probability of carotid intervention in minority hospitals (OR 0.81, 95% CI 0.70–0.93). In a continuous model, for every 10% increase in the proportion of minority patients, the odds of carotid treatment fell by 3% (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.94–1.00). Among racial/ethnic groups, blacks seem to be most affected by this disparity in care. In response, Dr. Joshua Willey comments on the overall low rate of predicted carotid revascularization, even among white patients at white-predominant hospitals (<25%), and the potential for classification errors using International Classification of Diseases, Ninth Revision (ICD-9) codes (which may have captured patients with low-grade carotid stenosis and patients with intracranial stenosis—which is known to preferentially affect certain minority groups more so than whites). The authors respond that the ICD-9 inclusion criteria were highly specific to patients with symptomatic, extracranial internal carotid artery stenosis, although they concede some patients may have had <50% stenosis. They reiterate that the novel finding is not the undertreatment of minority groups when treatment is indicated, but that hospitals serving minority communities are less likely to offer this care.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009445hwp:resource-id:neurology;94/20/896American Academy of Neurology2020-05-19DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9420896896
hw_mjid:neurology;94/20/896
http://n.neurology.org/cgi/content/short/94/20/896-a?rss=1
I read the article by Faigle et al.1 about the overall low rates of revascularization for symptomatic carotid stenosis in all groups of patients. Even under the best scenario of whites in a predominantly white-serving hospital, the predicted rates were <25% (table 3),1 suggesting a broad underutilization of this procedure nationwide and even more so in underserved hospitals and groups in the population. Our local practice includes carotid endarterectomy (CEA)/carotid artery stenting (CAS) in all high-grade symptomatic patients within 3 days after an infarct, unless the stroke is major and disabling or the patient refuses. With this in mind, and because rates were so low in this case series, methodologic issues in the study may exist. There likely is misclassification of patients as having symptomatic high-grade internal carotid artery (ICA) stenosis that requires intervention by using International Classification of Diseases, Ninth Revision, Clinical Modification codes 433.11 and 433.31 only—the validity of this code for high-grade symptomatic stenosis was not described, and this would also have been helpful information for codes on CEA/CAS. These codes likely include low-grade stenosis, which can be used by coders to justify 433.xx, as well as potentially intracranial ICA stenosis, for which revascularization is not indicated, and are more likely to be present in nonwhites. The probability of misclassification of mild stenosis or of intracranial artery stenosis (patients who should not be undergoing revascularization; more likely nonwhite), as CEA/CAS candidates, is a likely source of bias and could explain the results. Whites are also more likely to undergo CEA/CAS if asymptomatic,2 potentially due to socioeconomic factors, and the 433.xx has been used for asymptomatic patients to justify treatment or after developing a postoperative stroke.3 Last, patients who were transferred were excluded, but the reason for transfer was not explored; if they had symptomatic disease that needed surgery, they were indeed treated appropriately by the hospital that was otherwise low performing.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009446hwp:resource-id:neurology;94/20/896-aAmerican Academy of Neurology2020-05-19DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9420896897
hw_mjid:neurology;94/20/896-a
http://n.neurology.org/cgi/content/short/94/20/897?rss=1
We respectfully disagree with Dr. Willey's conclusions about our study.1 The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes used in our study (433.11 and 433.31) do not apply to asymptomatic internal carotid artery (ICA) stenosis and only capture extracranial disease resulting in infarction.2,3 Therefore, racial differences in the prevalence of intracranial disease or in the use of carotid endarterectomy (CEA) or carotid artery stenting (CAS) in asymptomatic ICA stenosis are an unlikely source of bias. The included ICD-9-CM codes indeed also capture patients with <50% stenosis or complete ICA occlusions, for whom revascularization would not be appropriate. We acknowledge this in the discussion as a well-known limitation of the data source; this has also been commented on elsewhere.4 However, it is important to distinguish differences between white and minority patients from differences between white and minority hospitals. Our results describe the latter and are adjusted for, and therefore independent of, individual patient race and other socioeconomic covariates. In other words, differences in eligibility by individual patient race/ethnicity may in part explain within-hospital differences between white and minority patients but would not explain between-hospital differences among patients of the same race. Figure 3 shows that the between-hospital difference in carotid revascularization is driven by lower odds of CEA/CAS in whites and Hispanics in minority, compared with white, hospitals. Individual-level racial differences in eligibility would not explain why white patients in minority-serving hospitals have lower adjusted odds of CEA/CAS than white patients in white hospitals or why Hispanic patients in minority-serving hospitals have lower adjusted odds of CEA/CAS than Hispanic patients in white hospitals. Last, we did not exclude transferred patients as suggested by Dr. Willey. Rather, we excluded records of patients transferred out to another acute care hospital while including those who were transferred in. Since the unit of observation in the data source is hospitalization, this is common practice to prevent double counting of transferred patients who may have 2 hospitalizations pertaining to the same event; this reduces rather than introduces bias.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009447hwp:resource-id:neurology;94/20/897American Academy of Neurology2020-05-19DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9420897897
hw_mjid:neurology;94/20/897
http://n.neurology.org/cgi/content/short/94/20/897-a?rss=1
According to epidemiologic data, use of β2-adrenoreceptor agonists has been associated with a significant, and dose-dependent, lower risk of Parkinson disease (PD). Similarly, β2 antagonists have been associated with a higher risk of developing α-synucleinopathy. In an attempt to corroborate these findings, Drs. Hopfner et al. examined population-based data from the Danish health registries. The investigators observed that β2 antagonist use was strongly associated with PD risk, whereas β2 agonists strongly correlated with a lower PD risk. However, potential confounders to these results are the following novel observations: First, driving the effect of β2 antagonists and later PD is the use of propranolol, which the investigators believe may have been used (perhaps incorrectly) to treat essential tremor (ET). Thus, the authors contend that early PD may have been misdiagnosed as ET in these cases. Second, the most common indication for inhaled β2 agonist use in an older population is chronic obstructive pulmonary disease due to tobacco use. As cigarette use has been associated with a reduced risk of PD, it may be that smoking is the actual factor related to the development of PD and not β2 agonist use. Supporting this claim are the findings that COPD diagnosis and use of inhaled anticholinergics were also inversely and independently related to PD. That said, the use of a β2 agonist remains a significant negative predictor of PD in the fully adjusted model, as was noted by Drs. Scherzer et al. in their comment. Drs. Scherzer et al. also maintain that other large studies (which adjusted for tobacco use) have corroborated the β2 agonist hypothesis. The original authors stand by their conclusions that a relationship cannot be decisively confirmed in the present data set given that biomarkers of long-term smoking significantly interact with their outcomes, and that a dose-response and temporal relationship between β2AR remains ambiguous.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009450hwp:resource-id:neurology;94/20/897-aAmerican Academy of Neurology2020-05-19DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9420897898
hw_mjid:neurology;94/20/897-a
http://n.neurology.org/cgi/content/short/94/20/898?rss=1
This Danish study1 "confirmed (β2-adrenoreceptor [β2AR]) agonist use to be associated with reduced Parkinson disease (PD) risk...," replicating larger studies in Israel2 and Norway.3 However, the authors' speculations regarding causality, and that smoking may confound the association, conflict with their own study. First, they did not collect smoking data. In Israel,2 the association remained significant after directly adjusting for smoking (which was collected) and smoking-related covariates. Second, even after adjusting for COPD diagnosis, inhaled corticosteroids, and inhaled anticholinergics (their "markers of smoking"), β2AR agonists were significantly associated with reduced PD risk with an OR of 0.64 (0.42–0.98) compared with 0.66 (0.52–0.85) without adjusting (table 4).1 Adjusting for the smoking markers did not attenuate the OR. Once these covariates are statistically controlled, any remaining significant relation between β2AR agonists and reduced PD risk cannot be due to their mediating effects. Whether covariates themselves are related to PD risk is not directly relevant. Third, the beta-blocker propranolol, which increased neuronal SNCA,3 was associated with increased PD risk in Denmark (excluding essential tremor),1 Norway (restricted to cardiovascular indications),3 and Israel (5–8 years lag).2 Finally, β2AR agonists, associated with reduced PD risk after adjusting for smoking-related covariates in Norway,3 Israel,2 and Denmark,1 offered neuroprotection in 3 rodent models.3–5 Thankfully, rodents don't smoke.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009449hwp:resource-id:neurology;94/20/898American Academy of Neurology2020-05-19DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9420898899
hw_mjid:neurology;94/20/898
http://n.neurology.org/cgi/content/short/94/20/899?rss=1
We appreciate the comments from Drs. Scherzer, Riise, and Locascio on our article1 on the effects of β2-adrenoceptor (β2AR) antagonists and agonists and risk of Parkinson disease (PD). Since the initial publication,2 this hypothesis has been scrutinized by multiple groups, yielding conflicting results.2–5
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009448hwp:resource-id:neurology;94/20/899American Academy of Neurology2020-05-19DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9420899899
hw_mjid:neurology;94/20/899
http://n.neurology.org/cgi/content/short/94/20/900?rss=1
In the article "Potential for treatment benefit of small molecule CGRP receptor antagonist plus monoclonal antibody in migraine therapy" by Mullin et al.,1 first published online January 13, 2020, the last sentence of the abstract's Results should read "While using rimegepant alone or together with erenumab, patients reported no related adverse events." The sentence appears correctly in the May 19, 2020, issue. The authors regret the error.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009280hwp:master-id:neurology;WNL.0000000000009280American Academy of Neurology2020-05-19CORRECTIONS9420900900
hw_mjid:neurology;94/20/900
http://n.neurology.org/cgi/content/short/94/20/900-a?rss=1
2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009279hwp:master-id:neurology;WNL.0000000000009279American Academy of Neurology2020-05-19CORRECTIONS9420900900
hw_mjid:neurology;94/20/900-a
http://n.neurology.org/cgi/content/short/94/20/e2076?rss=1
Objective

Patients were matched on demographics and level of global cognitive impairment. Patterns of cross-sectional performance and longitudinal decline were examined in 4 cognitive domains: Visuospatial, Memory, Executive, and Language. Power analyses were performed to determine the numbers of participants needed to adequately power a hypothetical clinical trial to slow cognitive decline in pure PDD, pure DLB, or a mixed PDD/DLB group.

Results

Both DLB and PDD were more impaired and declined more rapidly than AD in the Visuospatial domain. Patients with PDD exhibited the most impairment and fastest decline in Executive, although patients with DLB also declined faster than AD. Memory was more impaired in AD than DLB and in both compared with PDD; however, all 3 groups declined at comparable rates. In contrast, PDD declined at a slower rate on Language measures than DLB or AD. Power analyses suggest that Visuospatial and Executive outcome measures would be most sensitive in PDD, but Memory and Language in DLB.

Conclusion

DLB and PDD differ from each other, and from AD, in a cognitive domain-specific manner. As such, different outcome measures may be most sensitive to detecting changes in DLB vs PDD, suggesting that the 2 should be analyzed separately in clinical trials.

To investigate the association of triglyceride (TG) principal component scores with Alzheimer disease (AD) and the amyloid, tau, neurodegeneration, and cerebrovascular disease (A/T/N/V) biomarkers for AD.

Methods

Serum levels of 84 TG species were measured with untargeted lipid profiling of 689 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including 190 cognitively normal older adults (CN), 339 with mild cognitive impairment (MCI), and 160 with AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [18F]fluorodeoxyglucose-PET) were assessed with a generalized linear model approach. In both cases, the Bonferroni method of adjustment was used to correct for multiple comparisons.

This study shows that PUTG component scores were significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE 4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.

To evaluate the risk of death in relation to incident antiepileptic drug (AED) use compared with nonuse in people with Alzheimer disease (AD) through the assessment in terms of duration of use, specific drugs, and main causes of death.

Methods

The MEDALZ (Medication Use and Alzheimer Disease) cohort study includes all Finnish persons who received a clinically verified AD diagnosis (n = 70,718) in 2005–2011. Incident AED users were identified with 1-year washout period. For each incident AED user (n = 5,638), 1 nonuser was matched according to sex, age, and time since AD diagnosis. Analyses were conducted with Cox proportional regression models and inverse probability of treatment weighting (IPTW).

Results

Nearly 50% discontinued AEDs within 6 months. Compared with nonusers, AED users had an increased relative risk of death (IPTW hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.12–1.36). This was mainly due to deaths from dementia (IPTW HR, 1.62; 95% CI, 1.42–1.86). There was no difference in cardiovascular and cerebrovascular deaths (IPTW HR, 0.98; 95% CI, 0.67–1.44). The overall mortality was highest during the first 90 days of AED use (IPTW HR, 2.40; 95% CI, 1.91–3.03). Among users of older AEDs, relative risk of death was greater compared to users of newer AEDs (IPTW HR, 1.79; 95% CI, 1.52–2.16).

Conclusion

In older vulnerable patients with a cognitive disorder, careful consideration of AED initiation and close adverse events monitoring are needed.

This monocenter retrospective cohort study analyzed the data of 471 patients started on BoNT therapy between 1995 and 2015. Blood samples of 173 patients were investigated for NABs using the mouse hemidiaphragm test (93 with suspected therapy failure, 80 prospective study participants). The frequency of NAB-cSTF was assessed for various indications: hemifacial spasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. A priori defined potential risk factors for NAB-cSTF were evaluated, and a stepwise binary logistic regression analysis was performed to identify independent risk factors.

Results

Treatment duration was 9.8 ± 6.2 years (range, 0.5–30 years; adherence, 70.6%) and number of treatment cycles 31.2 ± 22.5 (3–112). Twenty-eight of 471 patients (5.9%) had NAB-cSTF at earliest after 3 and at latest after 103 treatment cycles. None of the 49 patients treated exclusively with incobotulinumtoxinA over 8.4 ± 4.2 (1–14) years developed NAB-cSTF. Independent risk factors for NAB-cSTF were high BoNT dose per treatment, switching between onabotulinumtoxinA and other BoNT formulations (except for switching to incobotulinumtoxinA), and treatment of neck muscles.

Conclusions

We present a follow-up study with the longest duration to date on the incidence of NAB-cSTF in patients treated with various BoNT formulations, including incobotulinumtoxinA. Whereas the overall risk of NAB-cSTF is low across indications and BoNT formulations, our findings underpin the recommendations to use the lowest possible dose particularly in cervical dystonia, and to avoid unnecessary switching between different formulations.

To provide the first clinical report that 2 calcitonin gene-related peptide (CGRP) therapies, a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody, can be used concomitantly to treat refractory migraine.

Methods

Case reports are presented of 2 patients participating in a long-term safety study of rimegepant 75 mg oral tablets for acute treatment (NCT03266588). After Food and Drug Administration approval of erenumab, both patients started subcutaneous erenumab monthly as allowed per protocol.

Results

Patients were women 44 and 36 years of age with ≥2 decades of self-reported suboptimal response to multiple migraine medications. Patient 1 used rimegepant for 6 months and then started erenumab 70 mg subcutaneous monthly. Despite a response to preventive treatment with erenumab, she experienced substantial relief treating 7 of 7 acute attacks with rimegepant and eliminated regular, frequent use of ibuprofen and a caffeinated analgesic. Patient 2 used rimegepant for 60 days before starting erenumab 140 mg subcutaneously monthly. While on erenumab, 9 of 9 attacks treated with rimegepant responded. She stopped near-daily use of injectable ketorolac and diphenhydramine. While using rimegepant alone or together with erenumab, patients reported no related adverse events.

Conclusions

Rimegepant 75 mg may be effective for acute treatment during concomitant erenumab preventive administration. The mechanism underlying the benefits of concomitant use of a small molecule CGRP receptor antagonist and an anti-CGRP receptor antibody is unknown and requires further study.

ClinicalTrials.gov identifier

NCT03266588.

Classification of evidence

This study provides Class IV evidence that for patients with migraine using erenumab, rimegepant is effective for acute treatment.

To evaluate whether structural and functional changes occur in the afferent visual system of patients with stiff-person syndrome (SPS) and whether these changes correlate with disease burden, given the high concentration of -aminobutyric acid receptors, which are generally thought to be involved in SPS pathogenesis, in the retina.

Methods

In this single-center, cross-sectional study, patients with SPS and healthy controls (HCs) underwent optical coherence tomography (OCT), with a subset undergoing high- and low-contrast visual acuity (VA) assessments. Burden of disease was assessed via the number of body regions affected. Individuals with uncontrolled hypertension or comorbid neurologic or ophthalmologic disorders were excluded. Statistical analyses were performed using mixed-effects linear regression models.

To investigate the causal relevance of current tobacco smoking for the risk of Parkinson disease (PD).

Methods

We compared the risks of death from PD with smoking habits in 30,000 male doctors in the British Doctors cohort study in 1951 and in survivors who had been resurveyed periodically for 5 decades. Cause-specific mortality was monitored for 65 years and included 283 deaths from PD. The relative risks (RRs) of PD (and 95% confidence intervals [CIs]) were estimated using Cox models for smoking habits (smoking status, amount smoked, and years since quitting) at baseline or updated habits at resurvey.

Results

The prevalence of current smoking declined progressively during follow-up from 67% to 8% between 1951 and 1998. The crude rates of PD death were lower in current smokers than in never smokers at baseline (30 vs 46/100,000 persons-years). After adjustment for age at risk, current smokers at baseline had a 30% lower risk of PD (RR 0.71; 95% CI 0.60–0.84), and continuing smokers classified using updated smoking habits at resurvey had a 40% lower risk (RR 0.60; 95% CI 0.46–0.77) of PD compared with never smokers. The risks of PD were inversely associated with the amount of tobacco smoked. The protective effect of current smoking vs never smoking for PD was attenuated by increasing duration since quitting smoking.

Conclusions

In contrast to previous suggestions, the present report demonstrates a causally protective effect of current smoking on the risk of PD, which may provide insights into the etiology of PD.

To define and validate criteria for accurate identification of EEG interictal epileptiform discharges (IEDs) using (1) the 6 sensor space criteria proposed by the International Federation of Clinical Neurophysiology (IFCN) and (2) a novel source space method. Criteria yielding high specificity are needed because EEG over-reading is a common cause of epilepsy misdiagnosis.

Methods

Seven raters reviewed EEG sharp transients from 100 patients with and without epilepsy (diagnosed definitively by video-EEG recording of habitual events). Raters reviewed the transients, randomized, and classified them as epileptiform or nonepileptiform in 3 separate rounds: in 2, EEG was reviewed in sensor space (scoring the presence/absence of each IFCN criterion for each transient or classifying unrestricted by criteria [expert scoring]); in the other, review and classification were performed in source space.

Results

Cutoff values of 4 and 5 criteria in sensor space and analysis in source space provided high accuracy (91%, 88%, and 90%, respectively), similar to expert scoring (92%). Two methods had specificity exceeding the desired threshold of 95%: using 5 IFCN criteria as cutoff and analysis in source space (both 95.65%); the sensitivity of these methods was 81.48% and 85.19%, respectively.

Conclusions

The presence of 5 IFCN criteria in sensor space and analysis in source space are optimal for clinical implementation. By extracting these objective features, diagnostic accuracy similar to expert scorings is achieved.

Classification of evidence

This study provides Class III evidence that IFCN criteria in sensor space and analysis in source space have high specificity (>95%) and sensitivity (81%–85%) for identification of IEDs.

Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS).

Methods

Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates.

We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.

To evaluate the risk of Guillain-Barré syndrome (GBS) following seasonal influenza vaccination based on French nationwide data.

Methods

All cases of GBS occurring in metropolitan France between September 1 and March 31 from 2010 to 2014 were identified from the French national health data system. Data were analyzed according to the self-controlled case series method. The risk period started 1 day after the patient received vaccine (D1) until 42 days after vaccination (D42). The incidence of GBS during this risk period was compared to that of the control period (D43–March 31). The incidence rate ratio (IRR) was estimated after adjusting for seasonality and presence or not of acute infections.

Results

Between September and March, of the 2010/2011 to 2013/2014 influenza vaccination seasons, 3,523 cases of GBS occurred in metropolitan France and were included in the study. Among them, 15% (527 patients) had received influenza vaccination. A total of 140 patients developed GBS during the 42 days following influenza vaccination. The crude risk of developing GBS was not significantly increased during the 42 days following influenza vaccination (IRR, 1.02; 95% confidence interval [CI], 0.83–1.25; p = 0.85). This result remained nonsignificant after adjustment for calendar months and the incidence of acute gastrointestinal and respiratory tract infections (IRR, 1.10; 95% CI, 0.89–1.37; p = 0.38). In contrast, the risk of GBS was fourfold higher after acute respiratory tract infection (IRR, 3.89; 95% CI, 3.52–4.30; p < 0.0001) or gastrointestinal infection (IRR, 3.64; 95% CI, 3.01–4.40; p < 0.0001).

Conclusions

No association between seasonal influenza vaccination and GBS was shown during the 42 days following vaccination.

]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009180hwp:master-id:neurology;WNL.0000000000009180American Academy of Neurology2020-05-19NULL HYPOTHESIS9420e2168e2179
hw_mjid:neurology;94/20/e2168
http://n.neurology.org/cgi/content/short/94/20/e2180?rss=1
A 48-year-old left-handed man presented to our emergency department (ED) with a 2-year history of auditory hallucinations that had become louder over several days.
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009440hwp:master-id:neurology;WNL.0000000000009440American Academy of Neurology2020-05-19RESIDENT &amp;amp; FELLOW SECTION9420e2180e2186
hw_mjid:neurology;94/20/e2180
http://n.neurology.org/cgi/content/short/94/20/e2187?rss=1
A 17-year-old girl presented with subacute decline in ambulation, ataxia, generalized weakness, dysphagia, and asymmetric hearing loss. MRI findings include abnormal signal in medial thalami, mesencephalon, posterior pons, and medulla oblongata (figure). Magnetic resonance spectroscopy showed elevated lactate and decrease in N-acetylaspartate (figure, F). DNA isolated from muscle biopsy showed A8344G mutation of mitochondrial DNA (tRNA [Lys] gene), associated with 80% of patients with myoclonic epilepsy with ragged-red fibers (MERRF). MERRF is a rare mitochondrial disorder with variable onset and clinical presentation. Neuroradiologic findings of MERRF are reported rarely, with brainstem and cerebellar degeneration being the main feature of MERRF.1
]]>2020-05-18T12:45:31-07:00info:doi/10.1212/WNL.0000000000009438hwp:master-id:neurology;WNL.0000000000009438American Academy of Neurology2020-05-19RESIDENT &amp;amp; FELLOW SECTION9420e2187e2188
hw_mjid:neurology;94/20/e2187
http://n.neurology.org/cgi/content/short/94/19/807?rss=1
2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009396hwp:resource-id:neurology;94/19/807American Academy of Neurology2020-05-12IN FOCUS9419807808
hw_mjid:neurology;94/19/807
http://n.neurology.org/cgi/content/short/94/19/809?rss=1
In 1896, Sir William Osler1 said, "Humanity has but three great enemies: fever, famine, and war; of these by far the greatest, by far the most terrible, is fever." This rings true even today.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009455hwp:master-id:neurology;WNL.0000000000009455American Academy of Neurology2020-05-12SPECIAL EDITORIALS9419809810
hw_mjid:neurology;94/19/809
http://n.neurology.org/cgi/content/short/94/19/811?rss=1
According to the World Health Organization, during the next few decades, the burden of cardiovascular and cerebrovascular diseases, the 2 leading causes of death globally, will increase further as the world population ages. Approximately one-fourth to one-third of people will die of acute vascular diseases.1 Thus, primary and secondary antithrombotic prevention plays a key role in reducing this burden. Prescription of oral anticoagulants has increased in recent years,2 with at least 4 new direct oral anticoagulants (DOACs) emerging as alternatives to warfarin in different clinical scenarios. Compared to warfarin, DOACs have reduced risk of major bleeding, especially intracranial hemorrhages. Therefore, DOACs have become the first-line treatment for stroke prevention in patients with nonvalvular atrial fibrillation.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009156hwp:master-id:neurology;WNL.0000000000009156American Academy of Neurology2020-05-12EDITORIALS9419811812
hw_mjid:neurology;94/19/811
http://n.neurology.org/cgi/content/short/94/19/813?rss=1
The rapid aging of our population has led to a growing proportion of elderly patients and those presenting with severe neurologic injury in the hospital. Because these patients frequently lack capacity, surrogate decision makers often shoulder the burden of having to decide between continued aggressive care vs withdrawal of life-sustaining therapies. There are scant data to guide the decision-making process in this increasingly common scenario. In this issue of Neurology®, Hwang et al.1 report a study aimed at identifying the most common concerns for surrogate decision makers when faced with the hypothetical situation of determining a plan of care for a neurologically devastated patient.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009395hwp:master-id:neurology;WNL.0000000000009395American Academy of Neurology2020-05-12EDITORIALS9419813814
hw_mjid:neurology;94/19/813
http://n.neurology.org/cgi/content/short/94/19/825?rss=1
The February 25, 2020, podcast interview highlighted an article on anticonvulsant medications for status epilepticus. For our What's Trending feature of the week, you'll hear an interview on the future of Neuroimmunology & Neuroinflammation.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009403hwp:resource-id:neurology;94/19/825American Academy of Neurology2020-05-12WHAT'S HAPPENING9419825825
hw_mjid:neurology;94/19/825
http://n.neurology.org/cgi/content/short/94/19/826?rss=1
Articles appearing in the December 2019 issue
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009408hwp:resource-id:neurology;94/19/826American Academy of Neurology2020-05-12WHAT'S HAPPENING9419826826
hw_mjid:neurology;94/19/826
http://n.neurology.org/cgi/content/short/94/19/827?rss=1
Brian C. Callaghan, MD, MS, and Kevin A. Kerber, MD, MS
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009404hwp:resource-id:neurology;94/19/827American Academy of Neurology2020-05-12WHAT'S HAPPENING9419827827
hw_mjid:neurology;94/19/827
http://n.neurology.org/cgi/content/short/94/19/828?rss=1
Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy described in 1916 by Guillain, Barré, and Strohl. However, many similar cases had been reported earlier under various terms, with less detail and with various explanations about its pathophysiologic origin. Based on the analysis of old articles, we propose an overview of the history of acute inflammatory polyradiculoneuropathy before the official description of GBS.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009401hwp:master-id:neurology;WNL.0000000000009401American Academy of Neurology2020-05-12HISTORICAL NEUROLOGY9419828835
hw_mjid:neurology;94/19/828
http://n.neurology.org/cgi/content/short/94/19/836?rss=1
First reported by Guillain, Barré, and Strohl during the Great War, the concept of "Guillain-Barré syndrome" (GBS) progressively emerged as a clinical entity in its own right. Despite many debates about its clinical and pathophysiologic characteristics, GBS is now recognized as a disease throughout the world. We describe here the main steps of the rich history of GBS, from 1916 to the present.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009402hwp:master-id:neurology;WNL.0000000000009402American Academy of Neurology2020-05-12HISTORICAL NEUROLOGY9419836840
hw_mjid:neurology;94/19/836
http://n.neurology.org/cgi/content/short/94/19/841?rss=1
A 50-year-old man with a history of IV drug use and cervical scars presented with acute disorientation and incoherent speech. A cerebral CT demonstrated a left middle cerebral artery (MCA) infarct with intracranial linear hyperdensity (figure, A). CT angiography revealed a broken needle in the left internal and external carotid arteries (figure, B); there was apparent needle migration into the MCA (figure, B). No MRI was performed; the magnetic field may have moved the intracranial needle. Cervical needle fragments were removed surgically. Broken needle cardiac embolization associated with IV drug use has been reported,1,2 but intracranial arterial migration is exceptional.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009413hwp:master-id:neurology;WNL.0000000000009413American Academy of Neurology2020-05-12NEUROIMAGES9419841842
hw_mjid:neurology;94/19/841
http://n.neurology.org/cgi/content/short/94/19/843?rss=1
An 81-year-old woman presented to the hospital after a week of intermittent episodes of decreased level of consciousness, right facial droop, and slurred speech, lasting approximately 30 minutes. Her medical history included chronic obstructive pulmonary disease, dyslipidemia, orthostatic hypotension, and 2 previous TIAs. She had fallen once in the preceding week, presumably as a result of her drowsiness. On examination, she was afebrile with a heart rate of 81 bpm and a blood pressure of 108/65 mm Hg. She was alert and cooperative, but disoriented to the year and location. Language examination was normal. Cranial nerves, motor, coordination, and sensory examinations were all normal without any focal deficits. However, when assessed during one of her episodes, she was less responsive, had decreased verbal output, and was noted to have a right facial droop. Basic serologic tests (complete blood count, electrolytes, renal function tests) were unremarkable. A head CT showed bilateral subarachnoid hemorrhage over the cerebral hemispheres without further abnormality.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009410hwp:master-id:neurology;WNL.0000000000009410American Academy of Neurology2020-05-12RESIDENT &amp;amp; FELLOW SECTION9419843848
hw_mjid:neurology;94/19/843
http://n.neurology.org/cgi/content/short/94/19/849?rss=1
In "Carotid plaques and detection of atrial fibrillation in embolic stroke of undetermined source," Ntaios et al. studied 777 patients with embolic stroke of undetermined source (ESUS) and found that the presence of ipsilateral nonstenotic carotid plaque was associated with a significantly lower likelihood for atrial fibrillation. Siegler et al. questioned the modality used to identify nonstenotic carotid plaque and paroxysmal atrial fibrillation, given that this affects incidence rates. Furthermore, they noted that although the authors commented on the frequency of conditions during which atrial fibrillation was detected (such as routine ECG, stroke recurrence, and myocardial infarction), it would have been useful to compare the incidence rates for patients with and without plaque. Ntaios responded that unfortunately, they did not have access to information about the technique used to diagnose carotid plaque or atrial fibrillation and that they did not think it was appropriate to compare the incidence of conditions during which atrial fibrillation was detected without this information. Lattanzi et al. commented that it would be useful to assess the relationship between plaques and atrial fibrillation and other variables, such as atrial cardiopathy, which has been shown to be inversely related to artery-to-artery strokes. Ntaios responded that they have performed additional analysis and hope to have their results published soon. It is clear that further research into workup and management of ESUS is needed.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009426hwp:resource-id:neurology;94/19/849American Academy of Neurology2020-05-12DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9419849849
hw_mjid:neurology;94/19/849
http://n.neurology.org/cgi/content/short/94/19/849-a?rss=1
We read with much interest the multicenter observational experience of Ntaios et al.1 regarding the incidence of atrial fibrillation among patients with embolic stroke of undetermined source (ESUS). The article added considerably to the increasing evidence regarding the heterogeneity of ESUS and the clinical relevance of nonstenotic carotid artery plaque.2,3 It may also assist in decision making regarding outpatient cardiac event monitoring.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009428hwp:resource-id:neurology;94/19/849-aAmerican Academy of Neurology2020-05-12DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9419849850
hw_mjid:neurology;94/19/849-a
http://n.neurology.org/cgi/content/short/94/19/850?rss=1
I would like to thank Dr. Siegler and colleagues for their kind words and for their thoughtful comments on our article.1 I agree that it would be useful to know which imaging modalities were used to assess carotid plaques; however, we did not register this information. Furthermore, we did not assess the type of modalities of heart rhythm monitoring that applied to our patients and therefore cannot provide information on whether they were used similarly between patients with or without carotid stenosis. I agree that it may be possible that these modalities were applied differently between these 2 groups. In this context, any comparison between these 2 groups about the incidence rates of the conditions during which atrial fibrillation was detected could lead to erroneous conclusions, which is why we refrained from providing these results in the article.1
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009427hwp:resource-id:neurology;94/19/850American Academy of Neurology2020-05-12DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9419850850
hw_mjid:neurology;94/19/850
http://n.neurology.org/cgi/content/short/94/19/850-a?rss=1
We read with great interest the article by Ntaios et al.,1 which demonstrated a lower cumulative probability of atrial fibrillation (AF) detection in patients with embolic strokes of undetermined source (ESUS) with ipsilateral nonstenotic carotid plaques compared with those without.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009430hwp:resource-id:neurology;94/19/850-aAmerican Academy of Neurology2020-05-12DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9419850851
hw_mjid:neurology;94/19/850-a
http://n.neurology.org/cgi/content/short/94/19/851?rss=1
I thank Dr. Lattanzi and Dr. Silvestrini for their interest in our work1 and their constructive suggestions. Several of the proposed analyses were already conducted and are currently under review in peer-reviewed journals. Hopefully, the results of these analyses will be publicly available soon.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009429hwp:resource-id:neurology;94/19/851American Academy of Neurology2020-05-12DISPUTES &amp;amp; DEBATES: EDITORS' CHOICE9419851851
hw_mjid:neurology;94/19/851
http://n.neurology.org/cgi/content/short/94/19/852?rss=1
In the article "Muscle and not neuronal biomarkers correlate with severity in spinal and bulbar muscular atrophy" by Lombardi et al.,1 the y-axis label for figure 2c should be "Creatinine (umol/L)." The editorial office regrets the error.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009392hwp:master-id:neurology;WNL.0000000000009392American Academy of Neurology2020-05-12CORRECTIONS9419852852
hw_mjid:neurology;94/19/852
http://n.neurology.org/cgi/content/short/94/19/852-a?rss=1
2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009541hwp:master-id:neurology;WNL.0000000000009541American Academy of Neurology2020-05-12CORRECTIONS9419852852
hw_mjid:neurology;94/19/852-a
http://n.neurology.org/cgi/content/short/94/19/852-b?rss=1
2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009543hwp:master-id:neurology;WNL.0000000000009543American Academy of Neurology2020-05-12CORRECTIONS9419852852
hw_mjid:neurology;94/19/852-b
http://n.neurology.org/cgi/content/short/94/19/e1968?rss=1
Objective

To assess the frequency and utilization trends of dabigatran reversal with idarucizumab and compare associated complications, outcomes, and door-to-needle times to those of patients not exposed to idarucizumab in a nationwide cohort of thrombolyzed patients over a 24-month period.

Methods

This is an observational cohort study of all New Zealand patients with stroke treated with stroke reperfusion entered into a mandatory online national registry. Each hospital records data including patient demographics, treatment delays, complications, 7-day outcomes, and idarucizumab use.

Results

Between 1 January 2017 and 31 December 2018, 1,336 patients received thrombolysis. Fifty-one patients received idarucizumab prior to thrombolysis (median [interquartile range] age 73 [57–83] years): 8 (1.3%) in 2017 and 43 (6%) in 2018 (p < 0.001). Over the same 24-month period, 386 patients had stroke clot retrieval, of whom 8 (2.1%) were first treated with idarucizumab. Idarucizumab-treated patients had slower door-to-needle times (83 [54–110] minutes vs 61 [43–85] minutes, p = 0.0006). Symptomatic intracerebral hemorrhage occurred in 2 (3.9%) of the idarucizumab-treated patients and 49 (3.8%) of the other thrombolyzed patients (p = 0.97). None of the idarucizumab-treated patients had significant thrombotic complications. At 7 days, 3 (5.9%) idarucizumab-treated and 101 (7.9%) of the other thrombolyzed patients had died (p = 0.61).

Conclusion

Idarucizumab was used in 6% of all thrombolyzed patients in a national cohort during 2018, up from 1.3% in 2017. Idarucizumab appeared to be safe with similar clinical outcomes to routinely managed patients, despite a 22-minute door-to-needle time delay. Idarucizumab can facilitate thrombolysis in patients with stroke taking dabigatran.

Classification of evidence

This study provides Class III evidence that idarucizumab use is associated with similar early post-thrombolysis outcomes compared with patients not exposed to this drug.

This study investigated the sex difference in prevalence of depression at 90 days after first-ever stroke.

Methods

Patients with first-ever stroke (n = 786) were identified from the population-based Brain Attack Surveillance in Corpus Christi project (2011–2016). Poststroke depressive symptoms were assessed by the 8-item Patient Health Questionnaire, and prestroke depression status (history and medication use) was self-reported. Logistic regression was used to examine the association between sex and depression after stroke, and effect modification by prestroke depression status, accounting for missing data.

Results

Women were more likely to have a history of and be on medication for depression at the time of stroke than men (p < 0.001). Prevalence of depression at 90 days was 28.2% for men (95% confidence interval [CI], 23.7%–32.8%) and 32.7% for women (95% CI, 27.8%–37.5%). The age-adjusted odds ratio (OR) of depression after stroke comparing women and men was 1.34 (95% CI, 0.97–1.85), and fully attenuated after adjustment for sociodemographic, stroke, and prestroke characteristics. Effect modification by prestroke depression status was present (p = 0.038). Among participants on medication for depression at the time of stroke, women were significantly less likely to have depression at 90 days compared with men (OR, 0.39; 95% CI, 0.16–0.96), whereas significant sex differences were not noted among those with and without a depression history.

Conclusion

The sex difference in prevalence of depression at 90 days after first-ever stroke was not significant overall, but varied by prestroke depression status. Interventions to address and prevent poststroke depression are needed, particularly among those with prestroke depression but not undergoing treatment for depression at stroke onset.

It is uncertain whether patients with cardioembolic stroke and without a guidance-based indication for statin therapy should be administered a statin for prevention of subsequent vascular events. This study was performed to determine whether the statin therapy is beneficial in preventing major vascular events in this population.

Methods

Using a prospective multicenter stroke registry database, we identified patients with acute cardioembolic stroke who were hospitalized between 2008 and 2015. Patients who had other established indications for statin therapy according to current guidelines were excluded. Major vascular event was defined as a composite of stroke recurrence, myocardial infarction, and vascular death. We performed frailty model analysis with the robust sandwich variance estimator using the stabilized inverse probability of treatment weighting method to estimate hazard ratios of statin therapy on outcomes.

Results

Of 6,124 patients with cardioembolic stroke, 2,888 (male 44.6%, mean age 75.3 years, 95% confidence interval [CI] 74.8–75.8) were eligible, and 1,863 (64.5%) were on statin therapy during hospitalization. After a median follow-up of 359 days, cumulative incidences of major vascular events were 9.3% in the statin users and 20.5% in the nonusers (p < 0.001 by log-rank test). The adjusted hazard ratios of statin therapy were 0.39 (95% CI 0.31–0.48) for major vascular events, 0.81 (95% CI 0.57–1.16) for stroke recurrence, 0.28 (95% CI 0.21–0.36) for vascular death, and 0.53 (95% CI 0.45–0.61) for all-cause death.

Conclusion

Starting statin during the acute stage of ischemic stroke may reduce the risk of major vascular events, vascular death, and all-cause death in patients with cardioembolic stroke with no guidance-based indication for statin.

To investigate whether in utero exposure to the Great Chinese Famine in 1959 to 1961 was associated with risk of intracerebral hemorrhage (ICH) in adulthood.

Methods

In this cohort analysis, we included 97,399 participants of the Kailuan Study who were free of cardiovascular disease and cancer at baseline (2006). Cases of incident ICH were confirmed by medical record review. We used the Cox proportional hazards model to calculate the hazard ratio (HR) and 95% confidence interval (CI) for ICH according to in utero famine exposure status.

Results

Among 97,399 participants in the current analyses, 6.3% (n = 6,160) had been prenatally exposed to the Great Chinese Famine. During a median 9.0 years of follow-up (2006–2015), we identified 724 cases of incident ICH. After adjustment for potential confounders, the HR of ICH was 1.99 (95% CI 1.39–2.85) for in utero famine-exposed individuals vs individuals who were not exposed to the famine. When exposure to famine and severity of famine were examined jointly, the adjusted HR was 2.99 (95% CI 1.21–7.39) for in utero exposure to severe famine and 1.94 (95% CI 1.32–2.84) for in utero exposure to less severe famine relative to those without exposure to famine.

Conclusions

Individuals with in utero exposure to famine, especially those exposed to severe famine, were more likely to have ICH in midlife, highlighting the role of nutritional factors in susceptibility to this severe cerebral condition.

To determine if survival and cognitive profile is affected by initial presentation in amyotrophic lateral sclerosis–frontotemporal dementia (ALS-FTD) (motor vs cognitive), we compared survival patterns in ALS-FTD based on initial phenotypic presentation and their cognitive profile compared to behavioral variant FTD (bvFTD).

Methods

Cognitive/behavioral profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD). The initial presentation of ALS-FTD was categorized into either motor or cognitive. Survival was calculated from initial symptom onset. MRI brain atrophy patterns were examined using a validated visual rating scale.

Initial motor presentation in ALS-FTD leads to faster progression than in those with a cognitive presentation, despite similar overall cognitive deficits. These findings suggest that disease progression in ALS-FTD may be critically linked to physiologic and motor changes.

To use network science to model complex diet relationships a decade before onset of dementia in a large French cohort, the 3-City Bordeaux study.

Methods

We identified cases of dementia incident to the baseline food frequency questionnaire over 12 years of follow-up. For each case, we randomly selected 2 controls among individuals at risk at the age at case diagnosis and matched for age at diet assessment, sex, education, and season of the survey. We inferred food networks in both cases and controls using mutual information, a measure to detect nonlinear associations, and compared food consumption patterns between groups.

Results

In the nested case-control study, the mean (SD) duration of follow-up and number of visits were 5.0 (2.5) vs 4.9 (2.6) years and 4.1 (1.0) vs 4.4 (0.9) for cases (n = 209) vs controls (n = 418), respectively. While there were few differences in simple, average food intakes, food networks differed substantially between cases and controls. The network in cases was focused and characterized by charcuterie as the main hub, with connections to foods typical of French southwestern diet and snack foods. In contrast, the network of controls included several disconnected subnetworks reflecting diverse and healthier food choices.

Conclusion

How foods are consumed (and not only the quantity consumed) may be important for dementia prevention. Differences in predementia diet networks, suggesting worse eating habits toward charcuterie and snacking, were evident years before diagnosis in this cohort. Network methods, which are designed to model complex systems, may advance our understanding of risk factors for dementia.

Vertex-wise interaction analyses revealed a differential relationship between carriers and noncarriers in the association between 11C-DED binding and estimated years to onset (EYO) and between cortical mean diffusivity (MD) and EYO. These differences were due to higher 11C-DED binding in presymptomatic carriers, with lower binding in symptomatic carriers compared to noncarriers, and to lower cortical MD in presymptomatic carriers, with higher MD in symptomatic carriers compared to noncarriers. Using a vertex-wise local correlation approach, 11C-DED binding was negatively correlated with cortical MD and positively correlated with cortical thickness.

Conclusions

Our proof-of-concept study is the first to show that microstructural and macrostructural changes can reflect underlying neuroinflammatory mechanisms in early stages of Alzheimer disease (AD). The findings support a role for neuroinflammation in AD pathogenesis, with potential implications for the correct interpretation of neuroimaging biomarkers as surrogate endpoints in clinical trials.

To evaluate the point of view of patients with Parkinson disease (PD) on early detection and risk disclosure in the prodromal phase of PD and to derive recommendations for an ethical framework for the recruitment of prodromal PD cohorts.

Methods

A standardized questionnaire to evaluate the patients' perception on early diagnosis in PD was designed by an interdisciplinary study group. After testing in a preliminary feasibility study (n = 20), the survey was performed retrospectively with patients from our clinic.

Results

A total of 101 patients with PD answered the questions. The majority of patients reported that time from onset of motor symptoms to diagnosis was burdensome, including false diagnoses and many consultations of various medical specialists. However, most of the patients evaluated early risk disclosure with skepticism. Freedom of choice and the potential of changes in lifestyle were rated as important.

Conclusion

Although patients with PD reported the time to diagnosis retrospectively as burdensome, the majority was skeptical regarding early disclosure of risk, especially with regard to the lack of pharmacologic options. Circumstances under which early detection and disclosure would have been approved by the majority of patients were (1) advice on lifestyle changes (exercise, nutrition) as potentially disease course–modifying therapy; (2) the establishment of an early diagnosis "culture," including early clarification of the patients' wish to know; and (3) regular support and follow-up of individuals after risk disclosure.

The symptomatic themes with the highest prevalence in HD were emotional issues (83.0%), fatigue (82.5%), and difficulty thinking (77.0%). The symptomatic themes with the highest relative importance to participants were difficulty thinking (1.91), impaired sleep or daytime sleepiness (1.90), and emotional issues (1.81). High Total Functional Capacity scores, being employed, and having prodromal HD were associated with a lower prevalence of symptomatic themes. Despite reporting no clinical features of the disease, prodromal individuals demonstrated high rates of emotional issues (71.2%) and fatigue (69.5%). There was concordance between the prevalence of symptoms reported by manifest individuals and caregivers.

Conclusions

Many symptomatic themes affect the lives of those with HD. These themes have a variable level of importance to the HD population and are identified both by those with HD and by their caregivers.

To determine whether groups of surrogates for patients with severe acute brain injury (SABI) with poor prognosis can be identified based on their prioritization of goals-of-care (GOC) decisional concerns, an online survey of 1,588 adults recruited via a probability-based panel representative of the US population was conducted.

Methods

Participants acted as a surrogate for a GOC decision for a hypothetical patient with SABI and were randomized to 1 of 2 prognostic scenarios: the patient likely being left with a range of severe functional disability (SD) or remaining in a vegetative state (VS). Participants prioritized a list of 12 decisional concerns via best-worst scaling. Latent class analysis (LCA) was used to discover decisional groups.

Results

The completion rate was 44.6%; data weighting was conducted to mitigate nonresponse bias. For 792 SD respondents, LCA revealed 4 groups. All groups shared concerns regarding respecting patient wishes and minimizing suffering. The 4 groups were otherwise distinguished by unique concerns that their members highlighted: an older adult remaining severely disabled (34.4%), family consensus (26.4%), doubt regarding prognostic accuracy (20.7%), and cost of long-term care (18.6%). For the 796 VS respondents, LCA revealed 5 groups. Four of the 5 groups had similar concern profiles to the 4 SD groups. The largest (29.0%) expressed the most prognostic doubt. An additional group (15.8%) prioritized religious concerns.

Conclusions

Although surrogate decision makers for patients with SABI are concerned with respecting patient wishes and minimizing suffering, certain groups highly prioritize other specific decisional factors. These data can help inform future interventions for supporting decision makers.

]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009406hwp:master-id:neurology;WNL.0000000000009406American Academy of Neurology2020-05-12ARTICLE9419e2054e2068
hw_mjid:neurology;94/19/e2054
http://n.neurology.org/cgi/content/short/94/19/e2069?rss=1
Iatrogenic injury of the marginal mandibular branch of the facial nerve is a rare complication of carotid endarterectomy and causes paresis of the ipsilateral lower lip.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009415hwp:master-id:neurology;WNL.0000000000009415American Academy of Neurology2020-05-12RESIDENT &amp;amp; FELLOW SECTION9419e2069e2071
hw_mjid:neurology;94/19/e2069
http://n.neurology.org/cgi/content/short/94/19/e2072?rss=1
We report a 15-year-old boy with a history of attention-deficit/hyperactivity disorder and new-onset generalized seizures, referred to our center for further evaluation. Examination was unremarkable, and EEG showed epileptiform K-complexes (figure) along with normal background activity. He was diagnosed with genetic generalized epilepsy (GGE) and managed with medication.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009414hwp:master-id:neurology;WNL.0000000000009414American Academy of Neurology2020-05-12RESIDENT &amp;amp; FELLOW SECTION9419e2072e2073
hw_mjid:neurology;94/19/e2072
http://n.neurology.org/cgi/content/short/94/19/e2074?rss=1
A 58-year-old woman presented with a 30-year history of progressive ataxia, dysarthria, and bilateral leg spasticity. Neurologic examination revealed involuntary movement of the uvula and soft palate at 2–3 Hz (video). Brain MRI showed only cerebellar atrophy (figure). Targeted next-generation sequencing identified a pathogenic homozygous variant in the SPG7 gene (c.773_774delTG; p.V258Gfs*30) leading to the diagnosis of spastic paraplegia type 7. Palatal tremor may be present in a variety of acquired or familial disorders1 such as cerebrotendinous xanthomatosis, SCA20, POLG-related disorders, neuroferritinopathy, and Alexander disease, but it was reported in only one patient with SPG7 mutations.2 Our observation confirms that SPG7 screening should be considered in patients with palatal tremor and ataxia.
]]>2020-05-11T12:45:31-07:00info:doi/10.1212/WNL.0000000000009409hwp:master-id:neurology;WNL.0000000000009409American Academy of Neurology2020-05-12RESIDENT &amp;amp; FELLOW SECTION9419e2074e2075
hw_mjid:neurology;94/19/e2074